Controlled releasing composition

ABSTRACT

A controlled releasing composition comprising a plurality of microparticles and a matrix as well as the preparation method thereof is disclosed. The plurality of microparticles comprise a first material and the matrix comprises a second material. The melting temperature of the first material is higher than the melting temperature of the second material.

FIELD OF THE INVENTION

The present disclosure relates generally to novel controlled releasecomposition comprising a matrix and a plurality of microparticlesoperably linked to the matrix, and methods of making and using the same.

BACKGROUND OF THE INVENTION

Many diseases or conditions require administration of a constant orsustained level of a medicament or biologically active agent to providethe optimal prophylactic or therapeutic effects. This can beaccomplished through a multiple dosing regimen or by employing a systemthat releases the medicament or biologically active agent in a sustainedor controlled fashion. The two main advantages of using controlledrelease pharmaceutical compositions are the ability to maintain anelevated therapeutic level over a prolonged period of time and anincrease in patient compliance obtained by reducing the number of dosesnecessary to achieve the same effect with a rapid-acting formulation.

Attempts to sustain medication levels include, for example, the use of acontrolled release composition comprising biodegradable materials, suchas polymeric compositions, containing the medicament. Polymericcontrolled delivery has significantly improved the success of many drugtherapies. In such a delivery system, pharmacokinetics andbiodistribution of the active agent depend upon the physiochemicalproperties and/or degradation properties of the polymer carriers. Theuse of these polymeric compositions, for example, in the form ofmicroparticles or microspheres, provides sustained release ofmedicaments.

Nonetheless, a number of issues hinder the applications ofmicroparticle-based controlled release composition. For example,microparticles have a tendency to form aggregates which cansignificantly affect the properties of the controlled releasecomposition. In addition, a large amount of solvent need to be added toa microparticle-based controlled release composition before itsapplication, generally with a ratio of 80-90%:10-20%, respectively,which can be very problematic in situations, such as, when injecting themicroparticle-based controlled release composition into a solid tumor.Furthermore, microparticles could move relatively easily within a tissueafter its implantation. This makes it impractical, if not impossible,for the measurement of the drug release rate in tissues near theimplantation site. Therefore, there exists a need for an improvedmicroparticle-based controlled release composition.

SUMMARY OF THE INVENTION

Provided herein are controlled release compositions and methods ofpreparing the same. Methods of use of the controlled releasecompositions for treating/preventing/diagnosing conditions in humans oranimals are also provided.

In one aspect, the present disclosure provides a controlled releasecomposition comprising a plurality of microparticles operably linked toa matrix, wherein:

the plurality of microparticles comprise a first material and a firstactive agent;

the matrix comprises a second material;

the first material comprises an initial melting temperature T_(H);

the second material comprises a complete melting temperature T_(L);

ΔT=T_(H)−T_(L); and

ΔT>0.

In certain embodiments, the first material or the second material is apolymer or a non-polymeric organic compound. In certain embodiments, thefirst material and the second material are either a polymer or anon-polymeric organic compound. In certain embodiments, the firstmaterial is a polymer and the second material is a non-polymeric organiccompound. In certain embodiments, the first material is a non-polymericorganic compound and the second material is a polymer. In certainembodiments, the first material comprises a combination of a polymer anda non-polymeric organic compound. In certain embodiments, the secondmaterial comprises a combination of a polymer and a non-polymericorganic compound.

In certain embodiments, the first material and/or the second materialcomprises a polymer formed by at least one monomer independentlyselected from the group consisting of: L-lactic acid, saccharide,ethylene glycol oxalate, p-dioxanone, ε-caprolactone,ethylcyanoacrylate, butylcyanoacrylate, β-hydroxybutyrate,3-hydroxybutyrate, 4-hydroxyvalerate, 1,3-bis(carboxyphenoxy)propane,sebacic acid, D-glucose, acetate of glucose, glucose substituted withhydroxyl groups, glycolic acid, ε-caprolacton, 1,4-dioxan-2-one, sebacicanhydride, dodecanoic anhydride, ethylene glycol, oxyethylene,1,3-bis(carboxyphenoxy)propane, 3-hydroxybutyrate, 3-hydroxyvalerate,caprolactone, methyl methacrylate, gelatin, isoleucine, leucine,alanine, asparagine, lysine, methionine, aspartic acid, cysteine,tryptophan, valine, glycine, proline, serine, tyrosine, arginine,histidine, phenylalanine, glutamic acid, threonine, glutamine, adenine,guanine, thymine, cytosine and dimethyl siloxane.

In certain embodiments, the first material and/or the second materialcan be independently selected from the group consisting of poly(L-lacticacid), dextran, poly(ethylene glycol oxalate),poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate),poly(butylcyanoacrylate), poly (β-hydroxybutyrate),poly(3-hydroxybutyrate-co-4-hydroxyvalerate),poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol,cellulose acetate, hydroxypropyl methyl cellulose phthalate, zein,poly(L-lactic-co-glycolic acid), poly(ε-caprolacton),poly(1,4-dioxan-2-one), poly(sebacic anhydride), poly(dodecanoicanhydride), poly(ethylene glycol), polyoxyethylene, stearic acid,stearyl alcohol; ethylene glycol palmitostearate, cetyl esters wax,poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid),poly(3-hydroxybutyrate-co-3-hydroxyvalerate), Carnauba wax,ethylcellulose, octadecanol, polycaprolactone, poly(methylmethacrylate), poly(gelatin), and silicone rubber.

In certain embodiments, the ΔT can be ≧2° C. In certain of theseembodiments, the ΔT can be ≧5° C., in other embodiments, ≧10° C., ≧20°C., ≧30° C., ≧40° C., or ≧50° C.

In certain embodiments, at least one of the first material and thesecond material is biodegradable. In certain embodiments, the firstmaterial is biodegradable. In certain embodiments, the second materialis biodegradable. In certain embodiments, the second material degradesfaster than the first material.

In certain embodiments, at least one of the plurality of microparticlesfurther comprises a first additive. In certain embodiments, at least oneof the plurality of microparticles further comprises a coating.

In certain embodiments, at least one of the plurality of microparticlescomprises about 2% to about 98% of the first material, about 2% to about98% of the first active agent, about 0% to about 30% of the firstadditive by weight.

In certain embodiments, the matrix further comprises a second activeagent. In certain embodiments, the matrix further comprises a secondadditive.

In certain embodiments, the controlled release composition comprisesabout 1% to about 95% of the microparticles, about 2% to about 98% ofthe second material, about 0% to about 70% of the second active agent,and about 0% to about 30% of the second additive by weight.

In certain embodiments, the plurality of microparticles can be uniformlydistributed or embedded in the matrix. In certain embodiments, theplurality of microparticles can be distributed or embedded in the matrixin accordance with a pre-determined pattern. In certain embodiments, theplurality of microparticles can be randomly distributed or embedded inthe matrix. In certain embodiments, the plurality of microparticles canbe coated on the surface of the matrix. In certain embodiments, aportion of the plurality of microparticles can be embedded within thematrix and the rest of the plurality of microparticles can be coated onthe surface of the matrix.

In certain embodiments, the controlled release composition furthercomprises a coating.

In certain embodiments, at least one of the plurality of microparticlescan be of a size of about 1 μm to about 5000 μm in diameter. In certainof these embodiments, at least one of the plurality of microparticlescan be of a size of about 20 μm to about 1000 μm, in other embodiments,about 50 μm to about 100 μm, or about 120 μm to about 1000 μm.

In certain embodiments, the controlled release composition can be of asize of about 0.2 mm to about 200 mm.

In another aspect, the present disclosure provides a method for making acontrolled release composition comprising a plurality of microparticlesoperably-linked to a matrix, wherein the method comprising:

preparing a plurality of microparticles comprising a first material anda first active agent; and

applying the plurality of microparticles to a matrix-forming compositioncomprising a second material, thereby forming the controlled releasecomposition, wherein:

the first material comprises an initial melting temperature T_(H);

the second material comprises a complete melting temperature T_(L);

ΔT=T_(H)−T_(L); and

ΔT>0.

In certain embodiments, the method further comprises heating thematrix-forming composition to a temperature T_(m), whereinT_(H)>T_(m)>T_(L). In certain embodiments, T_(H)−T_(m) and/orT_(m)−T_(L) can be ≧about 5° C., ≧about 10° C. or ≧about 20° C. Incertain embodiments, the method further comprises providing a coating tothe plurality of microparticles and/or the controlled releasecomposition.

In certain embodiments, the method further comprises dissolving thematrix-forming composition in a solvent, wherein the second material issoluble in the solvent while the first material or the microparticlescomprising the first material is substantially insoluble in the solvent.

In another aspect, the present disclosure provides a method of treatinga condition in a subject comprising administering to the subject thecontrolled release composition provided herein. In certain embodiments,the condition can be a pathological condition, a physiological conditionor a cosmetic condition.

Other features and advantages of the present disclosure will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating the preferred embodiments of the presentdisclosure, are given by way of illustration only, since various changesand modifications within the spirit and scope of the present disclosurewill become apparent to those skilled in the art from this detaileddescription.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a representative list of natural and semi-syntheticbiodegradable materials suitable for use in making a controlled releasecomposition in accordance with one embodiment of the present disclosure.

FIG. 2 shows a representative list of synthetic biodegradable materialssuitable for use in making a controlled release composition inaccordance with one embodiment of the present disclosure.

FIG. 3 shows a representative list of synthetic biodegradable materialssuitable for use in making a controlled release composition inaccordance with one embodiment of the present disclosure.

FIG. 4 shows a representative list of synthetic biodegradable materialssuitable for use in making a controlled release composition inaccordance with one embodiment of the present disclosure.

FIG. 5 shows a representative list of biodegradable materials suitablefor use in making a controlled release composition in accordance withone embodiment of the present disclosure.

FIG. 6 shows a representative list of organic compounds suitable for usein making a controlled release composition in accordance with oneembodiment of the present disclosure.

FIG. 7 shows a representative list of non-biodegradable materialssuitable for use in making a controlled release composition inaccordance with one embodiment of the present disclosure.

FIG. 8 shows a representative list of cyclodextrin materials suitablefor use in making a controlled release composition in accordance withone embodiment of the present disclosure.

FIG. 9 shows a representative list of materials suitable for use inmaking a controlled release composition in accordance with oneembodiment of the present disclosure.

FIG. 10 shows a representative list of poly(p-dioxanon-co-glycolide)polymers suitable for use in making a controlled release composition inaccordance with one embodiment of the present disclosure.

FIG. 11 shows a representative list of poly-(CPP-SA) polymers suitablefor use in making a controlled release composition in accordance withone embodiment of the present disclosure.

FIG. 12 shows a representative list of polyethylene glycol polymerssuitable for use in making a controlled release composition inaccordance with one embodiment of the present disclosure.

FIG. 13 shows a representative list of poloxamer polymers suitable foruse in making a controlled release composition in accordance with oneembodiment of the present disclosure.

FIG. 14 shows two schematic drawings illustrating the constitution of acontrolled release composition.

DETAILED DESCRIPTION OF THE INVENTION I. Controlled Release Composition

The controlled release compositions provided herein comprise a pluralityof microparticles operably linked to a matrix, wherein the plurality ofmicroparticles comprise a first material; the matrix comprises a secondmaterial; and the melting temperature of the first material is higherthan the melting temperature of the second material.

In one aspect, the present disclosure provides a controlled releasecomposition comprising a plurality of microparticles operably linked toa matrix, wherein the plurality of microparticles comprise a firstmaterial and a first active agent, and the matrix comprises a secondmaterial; the first material comprises an initial melting temperatureT_(H); the second material comprises a complete melting temperatureT_(L); ΔT=T_(H)−T_(L); and ΔT>0.

A. Materials

The controlled release composition comprises a first material, a secondmaterial and a first active agent. The first material and/or the secondmaterial can be any suitable material known in the art. The term“material” as used herein includes polymers, non-polymeric organiccompounds, and a combination thereof. In certain embodiments, the firstmaterial or the second material is a polymer or a non-polymeric organiccompound.

In certain embodiments, the first material comprises a polymer. Incertain embodiments, the second material comprises a polymer. Polymersinclude: 1) polymeric molecules comprising two or more repeating unitsbonded by covalent linkages, and 2) polymeric molecules formed fromsmall molecules by polymerization reaction. The repeating units ofpolymers can be any chemical compounds that are suitable for forming achemical union. The repeating units are also called monomer.Illustrative examples of monomers include alkanes, alkenes, alkynes,acids, alcohols, esters, amines, amides, ketones, ethers, anhydrides,nitrides, nucleotide, nucleic acid, amino acid, and saccharide. Incertain embodiments, a monomer itself can be a polymer. For example,gelatin, which comprises repeating units of amino acids, is itself apolymer (protein), but gelatin can be further crosslinked to form apoly(gelatin) comprising covalently linked aggregation of gelatin.

The first material and/or the second material in the present disclosurecan comprise a polymer formed by suitable monomers known in the art. Incertain embodiments, the monomer is independently selected from thegroup consisting of: L-lactic acid, saccharide, ethylene glycol oxalate,p-dioxanone, ε-caprolactone, ethyl cyanoacrylate, butylcyanoacrylate,β-hydroxybutyrate, 3-hydroxybutyrate, 4-hydroxyvalerate,1,3-bis(carboxyphenoxy)propane, sebacic acid, D-glucose, acetate ofglucose, glucose substituted with hydroxyl groups, glycolic acid,ε-caprolacton, 1,4-dioxan-2-one, sebacic anhydride, dodecanoicanhydride, ethylene glycol, oxyethylene, 1,3-bis(carboxyphenoxy)propane,3-hydroxyvalerate, caprolactone, methyl methacrylate, gelatin, aminoacid such as isoleucine, leucine, alanine, asparagine, lysine,methionine, aspartic acid, cysteine, tryptophan, valine, glycine,proline, serine, tyrosine, arginine, histidine, phenylalanine, glutamicacid, threonine, and glutamine, nucleotide such as adenine, guanine,thymine, cytosine and dimethyl siloxane.

The first material and/or the second material in the present disclosurecan comprise any suitable polymers known in the art. In certainembodiments, the first material and/or the second material can benatural polymers, semi-synthetic polymers, synthetic polymers, or acombination thereof. Natural polymers include polysaccharides (such asstarch, cellulose and gums), polypeptides, proteins, andpolynucleotides. Illustrative examples of natural polymers are, starch,dextrin, microcrystalline cellulose, acacia, chitosan, hyaluronic acid,alginate, dextran, tragacanth gum, xanthan gum, zein, collagen, gelatin,and shellac. More examples of natural polymers are provided in FIG. 1.Semi-synthetic polymers include a chemically modified naturallyoccurring polymer. Illustrative examples of semi-synthetic polymers arecross-linked starch, carboxymethyl cellulose, hydroxypropyl methylcellulose phthalate, and deacetylated-chitosan. More examples ofsemi-synthetic polymers are provided in FIG. 1. Synthetic polymers canbe any polymers formed by artificial polymerization of monomers.Examples of synthetic polymers are, polyoxyethylene,poly(L-lactic-co-glycolic acid), poly(lactic acid), andpoly(p-dioxanon-co-glycolide). More examples of semi-synthetic polymersare provided in FIGS. 2-5.

In certain embodiments, the first material and/or the second materialcomprise a polymer formed by the same repeating units or monomer(homopolymers). For example, poly(ethylene glycol) comprises repeatingunits of ethylene glycol. Homopolymers comprising the same monomer canhave various weight average molecular weight due to their differentpolymerization degrees, and consequently, may have various meltingtemperatures. For example, poly(ethylene glycol)s (PEGs) have a weightaverage molecular weight varying in a wide range such as PEG1000,PEG1500, PEG2000, PEG6000, and PEG20000.

In certain embodiments, the first material and/or the second materialcomprise a polymer formed by at least two different repeating units ormonomer (heteropolymer). For example, poly(L-lactic-co-glycolic acid)comprises repeating units of both L-lactic acid and glycolic acid.Heteropolymer comprising the same monomers can have various molefraction ratios of the monomers, and consequently, may have variousmelting temperatures. For example, poly(L-lactic-co-glycolic acid) has avaried mole fraction ratio of L-lactic acid to glycolic acid of 90:10,80:20, 75:25, 60:40, or 50:50.

In certain embodiments, the first material and/of the second materialcan be selected from any polymer listed in FIGS. 1-5 and FIGS. 7-13.

In certain embodiments, the first material comprises a non-polymericorganic compound. In certain embodiments, the second material comprisesa non-polymeric organic compound. The non-polymeric organic compoundsinclude any organic compounds that do not comprise repeating units.Illustrative examples of non-polymeric organic compounds include, fattyacids (such as stearic acid, citric acid), fatty alcohols (such ascholesterol, stearyl alcohol), fatty esters (such as ethylene glycolpalmitosterate, diethylene glycol palmitosterate, and glycerylbehenate), waxes (such as Carnauba wax, microcrystalline wax, and whitewax), and any suitable combinations. In certain embodiments, anon-polymeric compound can be a mixture comprising more than one organiccompound. For example, Carnauba wax comprises a combination of about80-85% of ester of fatty acids, 10-16% of fatty alcohols, 3-6% of acids,and 1-3% of hydrocarbons.

In certain embodiments, the first material and/or the second materialcan be selected from any non-polymeric organic compounds listed in FIG.6.

In certain embodiments, the first material comprises a polymer and thesecond material comprises a non-polymeric organic compound, or viceversa.

In certain embodiments, the first material comprises a combination of apolymer and a non-polymeric organic compound. In certain embodiments,the second material comprises a combination of a polymer and anon-polymeric organic compound.

The first material and/or the second material can be biodegradablematerials, non-biodegradable materials, or a combination thereof. Theterm “biodegradable material” refers to a material that is capable ofbeing completely or substantially degraded, eroded or absorbed whenexposed to either an in vivo environment or an in vitro environmenthaving physical, chemical, or biological characteristics substantiallysimilar to those of the in vivo environment within a living organism. Amaterial is capable of being degraded or eroded when it can be graduallybroken-down, resorbed, absorbed and/or eliminated by, for example,hydrolysis, enzymolysis, oxidation, metabolic processes, bulk or surfaceerosion, and the like within a living organism. The term “livingorganism” as used herein refers to human and animals. The biodegradablematerial degrades into non-toxic components in a living organism, andits degradation may not cause substantial tissue irritation or necrosisat the target tissue site. Illustrative examples of biodegradablematerials include, starch, zein, poly(lactic acid),poly(1,3-dioxan-2-one), poly(sebacic anhydride), alkoxy-polyphosphazene,poly(ether ester), poly(glutamic acid), poloxamer, cholesterol, stearicacid, and stearic alcohol. More examples of biodegradable materials areprovided in FIGS. 1-5. The non-biodegradable materials are material thatcannot be degraded in a living organism. Illustrative examples ofnon-biodegradable materials include poly(vinyl alcohol), poly(vinylacetate), polyurethane, and Carbomer. More examples of non-biodegradablematerials are provided in FIG. 7.

In certain embodiments, the first material and/or the second materialcan be independently selected from the group consisting of:poly(L-lactic acid), dextran, poly(ethylene glycol oxalate),poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate),poly(butylcyanoacrylate), poly (β-hydroxybutyrate),poly(3-hydroxybutyrate-co-4-hydroxyvalerate),poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol,cellulose acetate, hydroxypropyl methyl cellulose phthalate, zein,poly(L-lactic-co-glycolic acid), poly(ε-caprolacton),poly(1,4-dioxan-2-one), poly(sebacic anhydride), poly(dodecanoicanhydride), poly(ethylene glycol), polyoxyethylene, stearic acid,stearyl alcohol; ethylene glycol palmitostearate, cetyl esters wax,poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), andpoly(3-hydroxybutyrate-co-4-hydroxyvalerate), Carnauba wax,ethylcellulose, octadecanol, polycaprolactone, poly(methylmethacrylate), poly(gelatin), and silicone rubber.

In certain embodiments, the first material comprises a combination ofmore than one material. In certain embodiments, the first materialcomprises at least one of: (i) a combination of poly(L-lactic acid) andat least one compound selected from the group consisting of: dextran,poly(ethylene glycol oxalate), poly(p-dioxanone-co-ε-caprolactone),poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(β-hydroxybutyrate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate),poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol,cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein;(ii) a combination of poly(ethylene glycol oxalate) and at least onecompound selected from the group consisting of: dextran,poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate),poly(butylcyanoacrylate), poly (β-hydroxybutyrate),poly(3-hydroxybutyrate-co-4-hydroxyvalerate),poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol,cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein;(iii) a combination of poly(β-hydroxybutyrate) and at least one compoundselected from the group consisting of: dextran,poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate),poly(butylcyanoacrylate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate),poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol,cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein;(iv) a combination of poly(1,3-bis(carboxyphenoxy)propane-co-sebacicacid) and at least one compound selected from the group consisting of:dextran, poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate),poly(3-hydroxybutyrate-co-4-hydroxyvalerate), cholesterol, celluloseacetate, hydroxypropyl methyl cellulose phthalate, and zein; and (v) acombination of poly(butylcyanoacrylate) and at least one compoundselected from the group consisting of: dextran,poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate),poly(3-hydroxybutyrate-co-4-hydroxyvalerate),poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol,cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein.

In certain embodiments, the second material comprises a combination ofmore than one material. In certain embodiments, the second materialcomprise at least one of: (i) a combination of poly(L-lactic-co-glycolicacid) and at least one compound selected from the group consisting of:poly(ε-caprolacton), poly(1,4-dioxan-2-one), poly(sebacic anhydride),poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene,stearic acid, stearyl alcohol; ethylene glycol palmitostearate, cetylesters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), andpoly(3-hydroxybutyrate-co-3-hydroxyvalerate); (ii) a combination ofpoly(c-caprolacton) and at least one compound selected from the groupconsisting of: poly(1,4-dioxan-2-one), poly(sebacic anhydride),poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene,stearic acid, stearyl alcohol; ethylene glycol palmitostearate, cetylesters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), andpoly(3-hydroxybutyrate-co-3-hydroxyvalerate); (iii) a combination ofpoly(1,4-dioxan-2-one) and at least one compound selected from the groupconsisting of: poly(sebacic anhydride), poly(dodecanoic anhydride),poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol;ethylene glycol palmitostearate, cetyl esters wax,poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), andpoly(3-hydroxybutyrate-co-3-hydroxyvalerate); and (iv) a combination ofpoly(sebacic anhydride) and at least one compound selected from thegroup consisting of: poly(dodecanoic anhydride), poly(ethylene glycol),polyoxyethylene, stearic acid, stearyl alcohol; ethylene glycolpalmitostearate, cetyl esters wax,poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), andpoly(3-hydroxybutyrate-co-3-hydroxyvalerate).

In certain embodiments, the microparticle or the matrix comprises ahomogenous material, or a heterogeneous material. The homogeneousmaterial is a material comprising the same polymer, the same repeatingunits, or the same non-polymeric organic compound. The heterogeneousmaterial is a material comprising different polymers, differentmonomers, different non-polymeric organic compounds, or a combinationthereof.

B. Melting Temperature

The first material and the second material can be selected according totheir melting temperatures. The term “melting temperature” can beconstrued broadly in the present disclosure to include the followingtemperatures: 1) melting temperature at which the solid form of thematerial is in equilibrium with the liquid form of the material; 2)softening temperature at which the solid material softens; and 3)decomposition temperature at which the chemical structure of thematerial changes. It is well known in the art that when under heatexposure, solid materials melt and transform into its liquid form, orsoften and decompose without generating any liquid form of the material,or decompose without softening or melting. Melting generally takes placeover a temperature range at which the solid is in equilibrium with itsliquid, and as the temperature rises, the solid eventually changes toits liquid. Some materials do not melt but softens over a temperaturerange. Softening temperature is generally determined by slowly heatingthe testing material under a constant load until it experiences acertain deformation. Decomposition takes place above a certaintemperature where the chemical structure of the material changes (forexample, breaks down or gets oxidized).

Melting temperature of a polymer can be related to its molecular weightand its monomer composition. In certain embodiments, homopolymers havingdifferent molecular weights have different melting temperatures. Forexample, poly(ethylene glycol)s having molecular weights of 10³,1.5×10³, 2×10³ and 3×10³ have melting temperatures of 37-40° C., 44-48°C., 45-50° C., and 48-54° C., respectively. More examples are providedin FIGS. 8, 9, 12, and 13. In certain embodiments, heteropolymers havingdifferent mole fraction ratios of the monomers have different meltingtemperatures. For example,poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid)s with a molefraction ratio of 1,3-bis(carboxyphenoxy)propane to sebacic acid of4:96, 22:78, 41:59, and 60:40 have melting temperatures of 76° C., 66°C., 178° C., and 200° C., respectively. More examples are provided inFIGS. 9-11.

The first material and the second material can be selected according totheir initial melting temperatures (Ti) and their complete meltingtemperatures (Tc). The term “initial melting temperature (Ti)” refers tothe temperature at which 1) the material sample first begins to liquefyif the material melts, or 2) the material sample first begins to softenif the material softens but does not melt, or 3) the material samplefirst begins to decompose if the material does not soften or melt. Theterm “complete melting temperature (Tc)” refers to the temperature atwhich 1) the entire material sample becomes liquid if the materialmelts, or 2) the material sample first begins to decompose if thematerial does not melt.

In certain embodiments, the material is homogeneous, then Ti and Tc ofthe material is the Ti and Tc of the homogeneous material. In certainembodiments, the material is heterogeneous, and the Ti of the materialis the Ti of the material component having the lowest Ti, and the Tc ofthe material is the Tc of the material component having the highest Tc.In certain embodiments, the material is heterogeneous and the materialis a eutectic mixture, and the Ti of the material is the Ti of theeutectic melting temperature, and Tc of the material is the Tc of theeutectic melting temperature. “Eutectic mixture” refers to aheterogeneous material comprising more than one material components atsuch proportions that all the material components liquefy simultaneouslyat a temperature which is lower than the melting temperature of anyindividual component.

Ti and Tc can be determined using methods known in the art, for example,without limitation, differential scanning calorimetry (for review,please refer to: D. Braun et al, Polymer synthesis: theory and practice:fundamentals, methods, experiments, Published by Springer, 2005, Edition4, p 124-126; R. Koningsveld et al, Polymer phase diagrams: a textbook,Published by Oxford University Press, 2001, p 24), capillary tube basedmethods (see, for example, R. P. Brown et al, Handbook of polymertesting: physical methods, Published by CRC Press, 1999, p 348-349) ormicroscope-based methods (see, for example, A. K. Kolb et al, Automaticmicroscopic method for determination of melting point, Anal. Chem.,1967, 39(10): 1206-1208), Kofler hot-block based method, Vicat test,method of Martens, and heat distortion temperature measurement methods(see, for example, D. Braun et al, Polymer synthesis: theory andpractice: fundamentals, methods, experiments, Published by Springer,2001, Edition 3, p 86-88), decomposition vessel based methods, gaschromatography, thermogravimetric analysis (TGA), or TGA combined withmass spectrometry or TGA combined with FTIR spectroscopy (see, forexample, D. Braun et al, Polymer synthesis: theory and practice:fundamentals, methods, experiments, Published by Springer, 2001, Edition3, p 93-94; D. Braun et al, Polymer synthesis: theory and practice:fundamentals, methods, experiments, Published by Springer, 2005, Edition4, p 123-124).

The first material and the second material can be selected by thedifference in melting temperatures. In certain embodiments, ΔT iscalculated by the following equation:

ΔT=T _(H) −T _(L);

wherein T_(H) is the Ti of the first material, and T_(L) is the Tc ofthe second material.

In certain embodiments, the first material and the second material canbe selected so that their ΔT is ≧0° C. In certain embodiments, ΔT of thefirst material and the second material is ≧2° C. In certain embodiments,ΔT of the first material and the second material is ≧5° C. In certainembodiments, ΔT of the first material and the second material is ≧10° C.In certain embodiments, ΔT of the first material and the second materialis ≧20° C. In certain embodiments, ΔT of the first material and thesecond material is ≧30° C. In certain embodiments, ΔT of the firstmaterial and the second material is ≧40° C. In certain embodiments, ΔTof the first material and the second material is ≧50° C. Illustrativeexamples of pairs of the first material and the second material andtheir respective ΔT are shown in Table 1.

TABLE 1 Illustrative examples of the first material and the secondmaterial and their ΔT Ti Tc ΔT First material (° C.) Second material (°C.) (° C.) Carnauba wax 81 poly(lactide-co-glycolide acid) 79 2 (lactideacid/glycolide acid = 90/10) Carnauba wax 81 poly(lactide-co-glycolideacid) 76 5 (lactide acid/glycolide acid = 75/25) and stearic alcoholCarnauba wax 81 polycaprolactone 62 19 Poly(lactide acid) 162poly(lactide-co-glycolide acid) 76 86 (M_(w) = 2 × 10⁴) (lactideacid/glycolide acid = 75/25, M_(w) = 1.6 × 10⁴)

In certain embodiments, the first material and the second material canbe a pair of materials selected from the group consisting of:poly(L-lactic acid) and poly(L-lactic-co-glycolic acid); poly(L-lacticacid) and poly(ε-caprolacton); poly(L-lactic acid) andpoly(1,4-dioxan-2-one); poly(L-lactic acid) and poly(sebacic anhydride);poly(L-lactic acid) and poly(dodecanoic anhydride); poly(L-lactic acid)and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid);poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) andpoly(L-lactic-co-glycolic acid);poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) andpoly(ε-caprolacton); poly(1,3-bis(carboxyphenoxy)propane-co-sebacicacid) and poly(1,4-dioxan-2-one); poly(butylcyanoacrylate) andpoly(L-lactic-co-glycolic acid); poly(butylcyanoacrylate) andpoly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid);poly(ethylcyanoacrylate) and poly(L-lactic-co-glycolic acid);poly(ethylcyanoacrylate) andpoly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid); poly(ethyleneglycol oxalate) and poly(L-lactic-co-glycolic acid); poly(ethyleneglycol oxalate) and poly(ε-caprolacton); poly(ethylene glycol oxalate)and poly(1,4-dioxan-2-one); poly(ethylene glycol oxalate) andpoly(sebacic anhydride); poly(ethylene glycol oxalate) andpoly(dodecanoic anhydride); poly(ethylene glycol oxalate) andpoly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid); dextran andpoly(butylcyanoacrylate); dextran and poly(ethylcyanoacrylate); dextranand poly(L-lactic acid); dextran and poly(L-lactic-co-glycolic acid);dextran and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid);dextran and poly(sebacic anhydride); cellulose acetate and poly(L-lacticacid); cellulose acetate and poly(butylcyanoacrylate); cellulose acetateand poly(L-lactic-co-glycolic acid); cellulose acetate and poly(sebacicanhydride); cellulose acetate and poly(dodecanoic anhydride); Carnaubawax and poly(lactide-co-glycolide); ethylcellulose and octadecanol;Carnauba wax and polycaprolactone; poly(methyl methacrylate) andpoly(L-lactide); poly(lactide-co-glycolide) and poly(gelatin); siliconerubber and poly(L-lactide); ethylcellulose and a combination ofpoly(L-lactic-co-glycolic acid) and poly(ethylene glycol); a combinationof poly(L-lactic acid) and dextran and a combination ofpoly(L-lactic-co-glycolic acid) and poly(ethylene glycol); and dextranand a combination of poly(L-lactide) and poly(L-lactic-co-glycolicacid).

In certain embodiments, the first material and/or the second materialcan be further selected by their biodegradation rate. In certainembodiments, the first material and/or the second material can befurther selected so that the second material degrades faster than thefirst material.

In certain embodiments, the biodegradation rate of the first materialand/or the second material can be determined by measuring the rate ofweight loss of the material in a living organism. For example, the rateof weight loss can be measured by a method comprising: preparing animplant with the testing material, implanting a certain amount of suchmaterial implant in a living organism, and measuring the weight of theimplanted material after a specified time period.

In certain embodiments, the biodegradation rate of the first materialand/or the second material can be determined by measuring the rate ofintrinsic viscosity loss of the material in a living organism. Withoutbeing bound to theory, it is believed that the intrinsic viscosity is bedirectly related to the molecular weight of a material, in particular, apolymer. The rate of intrinsic viscosity loss of the material can bemeasured by a method comprising: preparing an implant with the testingmaterial, implanting a certain amount of such material implant in aliving organism, sampling a certain amount of the implant after aspecified time period and measuring the viscosity of both the implantedsample and the sample before implantation. The viscosity of the samplecan be measured using any suitable method known in the art, for exampleusing a glass viscometer such as Ostwald type viscometer and Ubbelohdetype viscometer (for review, please refer to: M. Chanda, Introduction topolymer science and chemistry: a problem solving approach, published byCRC Press, 2006, p 218-221).

In certain embodiments, the first material and the second material canbe further selected so that the second material degrades faster than thefirst material, wherein the first material is poly (L-lactide acid) andthe second material can be poly(lactide-co-glycolide acid).

C. Active Agent

The controlled release composition of the present disclosure can be apharmaceutical composition or a cosmetic composition. In certainembodiments, the controlled release composition can be an implantablepharmaceutical composition, such as, without limitation, a medicalimplant for treating cancer.

The controlled release composition of the present disclosure comprisesat least one active agent. In certain embodiments, the microparticles ofthe controlled release composition comprises a first active agent. Incertain embodiments, the matrix of the controlled release compositionfurther comprises a second active agent. In certain embodiments, thefirst active agent and/or the second active agent comprise one activeagent. In certain embodiments, the first active agent and/or the secondactive agent comprise a combination of at least two active agents. Incertain embodiments, the first active agent and the second active agentare the either the same or different. The term “active agent,” as usedherein, includes without limitation, pharmaceutically active agent,cosmetically active agent, physiologically active agent, or combinationsthereof. Exemplary active agents include, without limitation, drugs,medicines, medicaments, medications, remedies, biologicals, chemicalentities, new chemical entities, vaccines, herbal extracts, smallmolecule compounds, nucleic acids, polypeptides, antibodies orfunctional fragment thereof, polysaccharides, lipids, and combinationsthereof. Any active agent suitable for the purposes of the presentdisclosure known in the art can be used as the first active agent and/orthe second active agent.

Illustrative examples of pharmaceutically active agent include, withoutlimitation, local anesthetics, antiepileptic drugs and anticonvulsants,anti-alzheimer's disease drugs, analgesics, antipodagric,anti-hypertensive drugs, antiarrhythmic drugs, diuretic drugs, drugs fortreating liver diseases, drugs for treating pancreatic diseases,antihistamine drugs, anti-allergic drugs, glucocorticoid drugs, sexhormone drugs and contraceptive drugs, hypoglycemic drugs,anti-osteoporosis drugs, antibiotics, sulfonamides, quinolones, andother synthetic antibacterial drugs, antituberculous drugs, antiviraldrugs, anti-neoplasm drugs, and immunomodulators. Exemplary activeagents are listed in Table 2 in detail. Illustrative examples ofcosmetically active agents are also listed in Table 2.

TABLE 2 Class of active agents Exemplary active agents Local anestheticsprocaine hydrochloride, ropivacaine, oxybuprocaine hydrochloride,tetracaine hydrochloride, mepivacaine hydrochloride, benzocaine,cinchocaine hydrochloride, proxymetacaine, chloroprocaine hydrochloride,etidocaine hydrochloride, dyclonine hydrochloride, lidocainehydrochloride, prilocaine hydrochloride, bupivacaine hydrochlorideAntiepileptic drugs clonazepam, valproate sodium, halogabide andanticonvulsants Anti-alzheimer's huperzine a, rivastigmine,dihydroergotoxine mesilate, disease drugs nicergolin Analgesicsmorphine, dihydroetorphine hydrochloride, hydromorphone, sufentanilcitrate, alfentanil, remifentanil, buprenorphine hydrochloride,naloxone, nalmefene Antipodagric drugs colchicine Anti-hypertensivenifedipine, niludipine, verapamil, nitrendipine, nimodipine, drugsdiltiazem, lacidipine, nilvadipine, azelnidipine, amlodipine,felodipine, benidipine, nicardipine, isradipine, bepridil, nisoldipine,manidipine, nicorandil Antiarrhythmic drugs flestolol, verapamilhydrochloride Diuretic drugs cyclothiazide, methyclothiazide Drugs fortreating liver cucurbitacin, bifendate, sophora tonkinensis diseasesDrugs for treating octreotide pancreatic diseases Antihistamine drugschlorphenamine maleate, dimethindene maleate, clemastine fumarateAnti-allergic drugs ketotifen, azatadine maleate, levocabastineGlucocorticoid drugs medrysone, amcinonide, prednisone, clocortolonetrimethylacetic acid, triamcinolone acetonide, dexamethasone,mometasone, paramethasone, prednicarbate, budesonide, rimexolone,cloprednol, flunisolide, fludrocortisone, fluticasone Sex hormone drugsdiethylstilbestrol, nilestriol, epimestrol, estradiol, conjugated andcontraceptive estrogens, piperazine estrone, estradiol benzoate, drugschlorotrianisene, hydroxyestrone, estradiol valerate, mestranol,estrone, depo-estradiol, promestriene, dienestrol, estriol, fosfestrolsodium, quinestradol, ethinylestradiol, cyclofenil, prasterone,quinestrol, progesterone, ethisterone, hydroxyprogesterone,medroxyprogesterone, dydrogesterone, megestrol, chlormadinone,norethisterone, demegestone, medrogestone, noretynodrel, dienogest,nomegestrol, norgestrel, drospirenone, norgestimate, desogestrel,ethynodiol diacetate, norgestrienone, quingestanol, gestodene,promegestone, gestrinone, testosterone, danazol, metandienone,gonadorelin, goserelin Hypoglycemic drugs repaglinide, glibenclamide,voglibose, glimepiride Anti-osteoporosis teriparatide drugs Antibioticsbenzylpenicillin, procaine benzylpenicillin, benzathinebenzylpenicillin, benzylpenicillin v, phenoxymethylpenicillinhydrabamine, methicillin sodium, talampicillin, bacampicillinhydrochloride, lenampicillin hydrochloride, epicillin, ciclacillin,carbenicillin sodium, carfecillin sodium, carindacillin sodium,oxacillin sodium, nafcillin sodium, cloxacillin sodium, dicloxacillinsodium, flucloxacillin sodium, ampicillin, ticarcillin sodium,azlocillin sodium, mezlocillin sodium, piperacillin sodium, tazocillin,sulbenicillin sodium, mecillinam, sultamicillin, ampicloxacillin,amoxicillin, pivampicillin hydrochloride, hetacillin, metampicillin,pivmecillinam hydrochloride, apalcillin sodium, aspoxicillin, temocillinsodium, azidocillin, phenethicillin potassium, propicillin potassium,furbucillin, cefalotin sodium, cefaloridne, cefalexin, cefazolin sodium,cefradine, cefacetrile, cefroxadine, cefapirin sodium, ceftezole,cefathiamidine, cefadroxil, cefuroxime sodium, cefuroxime axetil,cefaclor, cefotiam hydrochloride, cefamandole, ceforanide, cefonicidsodium, cefprozil, cefminox sodium, cefoxitin sodium, cefmetazolesodium, cefotaxime sodium, cefoperazone sodium, sulperazon, ceftazidime,cefclidin, cefsulodin sodium, ceftriaxone sodium, ceftizoxime sodium,latamoxef disodium, flomoxef sodium, cefpimizole sodium, cefpirome,cefepime, cefuzonam, cefmenoxime, cefoselis sulfate, cefbuperazonesodium, cefcapene pivoxil, cefpiramide sodium, cefotetan disodium,cefodizime, ceftibuten, cefixime, cefetamet pivoxil, cefpodoximeproxetil, cefteram pivoxil, cefditoren pivoxil, cefdinir, imipenem,panipenem, meropenem, biapenem, faropenem, aztreonam, carumonam sodium,streptomycin sulfate, neomycin sulfate, paromomycin, lividomycin,astromicin sulfate, micronomicin sulfate, gentamicin sulfate, sisomicinsulfate, netilmicin sulfate, dibekacin sulfate, arbekacin sulfate,isepamicin, amikacin sulfate, kanamycin sulfate, tobramycin sulfate,ribostamycin sulfate, etimicin sulfate, spectinomycin, tetracyclinehydrochloride, oxytetracycline hydrochloride, doxycycline hydrochloride,minocycline hydrochloride, metacycline hydrochloride, demeclocyclinehydrochloride, guamecycline, chloramphenicol, chloramphenicol palmitate,chloramphenicol succinate, thiamphenicol, erythromycin, erythromycinlactobionate, erythromycin estolate, erythromycin ethylsuccinate,roxithromycin, midecamycin, midecamycin acetate, kitasamycin,kitasamycin tartrate, acetylkitasamycin, spiramycin, acetylspiramycin,azithromycin, clarithromycin, rokitamycin, josamycin, rosaramicin,dirithromycin, flutithromycin, telithromycin, lincomycin hydrochloride,clindamycin hydrochloride, clindamycin phosphate, vancomycinhydrochloride, norvancomycin, teicoplanin, polymyxin sulfate, polymyxine sulfate, colistimethate sodium, bacitracin, fosfomycin, fosfomycintrometamol, novobiocin sodium, linezolid, rifaximin, fusidate sodiumSulfonamides, sulfadiazine, sulfamethoxazole, trimethoprim,sulfafurazole, quinolones, and other sulfadimidine, sulfamonomethoxine,sulfadoxine, synthetic antibacterial sulfasalazine, sulfacetamidesodium, sulfadiazine silver, drugs nalidixic acid, pefloxacin, enoxacin,ofloxacin, ciprofloxacin, lomefloxacin, pipemidic acid, fleroxacin,grepafloxacin, gemifloxacin, rufloxacin, moxifloxacin, norfloxacin,pazufloxacin, trovafloxacin, sparfloxacin, tosufloxacin, levofloxacin,nitrofurantoin, furazolidone, nitrofural, metronidazole, tinidazole,berberine hydrochloride Antituberculous drugs rifampicin, rifandin,rifapentine, rifabutin, capreomycin, viomycin, cycloserine, isoniazid,ethambutol hydrochloride, aminosalicylate sodium, pyrazinamide Antiviraldrugs aciclovir, valaciclovir, penciclovir, famciclovir, ganciclovir,valganciclovir, foscarnet sodium, cidofovir, fomivirsen, idoxuridine,trifluridine, vidarabine, brivudine, zanamivir, oseltamivirAnti-neoplasm drugs methotrexate, edatrexate, lometrexol, trimetrexate,piritrexim, aminopterin sodium, fluorouracil, tegafur, carmofur,floxuridine, uft, altretamine, doxifluridine, tegadifur, mercaptopurine,tioguanine, azaguanine, sulfomercaprine sodium, pentostatin,hydroxycarbamide, hydroxyguanidine, cytarabine, ancitabine,capecitabine, enocitabine, gemcitabine, fludarabine phosphate,chlorambucil, methoxymerphalan, mechlorethaminoxide, sarcolysin,nitrocaphane, betamerphalan, ocaphane, formylmerphalan, glyfosfin,improsulfan tosilate, dianhydrodulcitol, dopan, carmustine,procarbazine, uramustine, lomustine, pipobroman, uraphetin, semustine,razoxane, nimustine, ethylenediamine tetraacetylimide, mannomustine,ranimustine, mitomycin, estramustine phosphate, fotemustine, cisplatin,prednimustine, streptozocin, carboplatin, iproplatin, oxaliplatin,nedaplatin, lobaplatin, iridium platinum, thiotepa, chlorozotocin,solaziquone, pcnu, triaziquone, dacarbazine, diaziquone, etoglucid,carboquone, busulfan, treosulfan, mitobronitol,, mitolactol,monocrotaline, bleomycin sulfate, bleomycin a5, boanmycin hydrochloride,etoposide, teniposide, chromomycin a3, plicamycin, peplomycin,hycanthone, camptothecin, hydroxycamptothecin, irinotecan, topotecan,daunorubicin, doxorubicin hydrochloride, pirarubicin, epirubicin,idarubicin hydrochloride, zorubicin hydrochloride, aclarubicin,detorubicin, aclacinomycin b, menogaril, piroxantrone, mitoguazonehydrochloride, mitoxantrone, bisantrene hydrochloride, amsacrine,nitracrine hydrochloride, dactinomycin, asparaginase, colchicine,colchiceinamide, vinblastine, vincristine, vindesine, vinorelbine,paclitaxel, docetaxel, harringtonine, homoharringtonine, emetinehydrochloride, aminoglutethimide, mitotane, tamoxifen, exemestane,toremifene citrate, formestane, anastrozole, flutamide, letrozole,fadrozole, bicalutamide, nilutamide, leuprorelin acetate, goserelinacetate, triptorelin, sizofiran, arsenic trioxide, cantharidin,norcantharidin, methylcantharidimide, nocardia rubra-cell wall skeleton,tretinoin, porfimer sodium, rituximab, trastuzumab, bortezomibImmunomodulators ciclosporin, tacrolimus, sirolimus, everolimus,gusperimus hydrochloride, mizoribine, azathioprine, mycophenolatemofetil, FTY720, cyclophosphamide, methotrexate, antithymocyte globulin,muromonab-cd3, daclizumab, basiliximab, anti-Rh antibody, anakinra,leflunomide, pimecrolimus, tripterygium glycosides, bacillus calmette-guerin vaccine, corynebacterium parvum vaccine, picibanil, ubenimex,muramyl dipeptide, broncho-vaxom, romurtide, coriolus versicolorpolysaccharide, lentinan, polyerga, biostim, transfer factor, thymosin,thymosinα1, thymopentin, levamisole, isoprinosine, ditiocarb sodium,pidotimod, polyinosinic acid-polycytidylic acid, polyactin a,aldesleukin, interferon Cosmetically active botulinum toxin, adenosintriphosphate (ATP), alpha agents glucosyl rutin, alpha hydroxy acids,alcohol, algae-extract, allantoin, aloe vera, amino acids, anti-ageingcomplex aquaspheres (vitamins E and F and unsaponifiables of olive oil),astringent agents avocado oil, aquaspheres, avocado oil, beeswax,beta-glucan, bio-cytokine, biodermin, biotin, bisabolol, butyl octanoicacid (BOA), borage oil, broadspectrum filter, burdock root extract,butcher's broom (Ruscus aculeatus, mausedorn), camellia kissi oil,ceramides, ceramide-lipid system, coconut oil, coenzyme Q, ubiquinone,coenzyme R, comfrey extract, contourmin (a complex based on barleyextract and escin), corn flower extract, cornstarch derivate, crystallipids, cucumber extract, cyclodermin, cyclodextrin, dihydroxyaceton(DHA), enzyme activating substances, juvena, erythru lose, erythulose,escin, essential fatty acids, eyebright extract, fatty acids,galactoarabian, gentian extract, ginseng extract, grape seed oil,hamamelis extract, hawkweed extract, Hibiscus esculentus seed extract,hibiscus flower acids, glycerin-acrylic acid polymer, ive transparentpigments, jojoba oil, kaolin, lactic acid, lecithin- complex (mixture oflecithin, phospholipid and other plant lipids), licorice extract,lipocer, algae extract, carnitin, coffein, lupin oil, lysin aspartat,macadamia oil, mallow extract, marine collagen, mate extract, nicotinicacid niacinamide, olive oil extract (unsaponifiables), pansy extract,pearlproteins, juvitacell, panthenol, pea extract, meadowfoam seed oil(limnanthes alba, sumpfblume), menthol, menthol derivative, micapigments, microfine pigments, honey extract, micro proteins, mintextract, mulberry extract, mushroom extract, pearly pigments, peelinggranules, phytoceramide phytosan, phytosterols, pineapple enzyme(bromelain), polymer pigments, hyaluronic acid, polysaccharides,prolactis, propantriol, proline, purcellin oil, peppermit oil, pyridoxin(vitamin 26), repair complex, saccarides, salicylic acid, silkprotein,huangquin root extract, subtilisin, shea butter, barley extract,mushroom extract, coffeine, soybean oil, soya proteins, squalan E,tanning accelerator tensides, titanum dioxide, tocopheryl acetate,vegetable proteins, extract from peas, vitamin A pure (retinol), vitaminA derivate, vitamin A palmitate, vitamin B6 (pyridoxine), vitamin Cpure - vitamin C (l-ascorbic acid), vitamin C-derivative, vitamin A,vitamin C, vitamin E, vitamin F, vitamin H, vitamin H with salt ofcitric acid, water lily root extract, wheat proteins, extracts ofmulberry (morus nigra), extracts of grapes (vitis vinifera) and extractsof baikal, skullcap (scutella baicalensis, helmetfiower), wild mangobutter, witch hazel extract, yeast extract

C. Microparticles and Matrix

The controlled release composition comprises a plurality ofmicroparticles operably linked to a matrix.

The plurality of microparticles comprises a first material and a firstactive agent. In certain embodiments, at least one of the plurality ofthe microparticles comprises a first material and a first active agent.The weight percentages of the first material and the first active agentin the microparticles can vary in any suitable ranges, and will beselected by a person skilled in the art as appropriate. In certainembodiments, at least one of the plurality of microparticles comprises aweight percentage of about 2% to about 98% of the first material, andabout 2% to about 98% of the first active agent. In certain embodiments,at least one of the plurality of microparticles comprises a weightpercentage of 20% to about 70% of the first material and about 30% toabout 80% of the first active agent.

In certain embodiments, the plurality of microparticles furthercomprises a first additive. Any additives suitable for the purposes ofthe present disclosure known in the art can be used. In certainembodiments, the additive can be a pharmaceutically acceptablesubstance, composition or vehicle. The additives involve in modifyingphysical and/or chemical properties of the controlled releasecomposition, regulating the release rate of the active agent, and/orapproximate to the physiological conditions of the body.

Each additive is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients, e.g. the materials and the activeagent, of the controlled release composition and suitable for use incontact with the tissue or organ of a living organism without excessivetoxicity, irritation, allergic response, immunogenicity, or otherproblems or complications, commensurate with a reasonable benefit/riskratio.

Any additives suitable for the purposes of the present disclosure can beused, for example, rate modifying agents, antioxidants, colorants,buffers, aromatics, colorants, flavor-improving agents, sweeteners,fillers, lubricants, isotonic agents, antimicrobial agents, anesthetics,preservatives, homogenization agents, toxicity adjusting agents,excipients, powders, salines, or other additives known in the art, orvarious combinations thereof.

Suitable rate modifying agents include, for example, sodiumcrosscaramellose, sodium carboxymethylcellulose, powdered cellulose,colloidal silicon dioxide, crospovidone, depolymerizable guar gum,magnesium aluminum silicate, methyl cellulose, alginic acid, calciumcarboxymethylcellulose, potassium polacrilin (and other cation exchangeresins such as Amberlite resins), starch, pregelatinized starch, sodiumstarch glycolate, sodium alginate, inorganic salts (e.g., sodiumchloride and potassium chloride), tweens, myrjs, sucrose, lactose,sorbitol, mannitol, fructose, glucose, dextran, fatty acid esters,inositol, magnesium stearate, zinc stearate, calcium stearate, gumArabic, and sodium alginate.

Suitable antioxidants include, for example, methionine, ascorbic acid,EDTA, sodium thiosulfate, platinum, catalase, citric acid, cysteine,thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxanisol,butylated hydroxytoluene, and/or propyl gallate. The reduction inoxidation prevents or reduces loss of binding affinity, therebyimproving stability of the composition and maximizing shelf-life.

Suitable fillers include, for example, talc, titanium dioxide, starch,kaolin, cellulose (microcrystalline or powdered) and combinationsthereof.

Suitable buffers include, for example, sodium acetate, sodium chloride,potassium chloride, calcium chloride, sodium lactate and the like, forapproximating the physiological conditions of the living organism.

Suitable lubricants include, for example, talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate.

The weight percentage of the additive in the microparticles ranges fromabout 0% to about 30%. In certain embodiments, the weight percentage ofthe additive in the microparticles ranges from about 0% to about 20%.

In certain embodiments, the plurality of microparticles can be furtherprovided with a coating. Without being bound to any theory, but it isbelieved that coating of microparticles can modify the mode of releaseof the active agent or modify the physical and/or chemical properties ofthe microparticles. For example, a coating modify the release rate ofthe active agent. For another example, a coating modify the opacity ofthe microparticles.

Any suitable coating substances can be used. In certain embodiments, thecoating substance comprises a sugar. In certain embodiments, the coatingsubstance comprises a polymer. In certain embodiments, the coatingsubstance further comprises a plasticizer to make the polymer in thecoating substance softer and more pliable. In certain embodiments, thecoating substance of the plurality of microparticles comprises a polymerwhose initial melting temperature is higher than the complete meltingtemperature of the second material contained in the matrix. In certainembodiments, the coating substance of the plurality of microparticlescomprises a colorant to protect the microparticles against lightexposure.

The weight percentage of the plurality of microparticles in thecontrolled release composition can vary in any suitable range. Incertain embodiments, the controlled release composition comprises aweight percentage of about 1% to about 95% of the plurality ofmicroparticles. In certain embodiments, the controlled releasecomposition comprises a weight percentage of about 20% to about 80% ofthe plurality of microparticles.

The matrix of the controlled release composition comprises a secondmaterial. In certain embodiments, the matrix further comprises a secondactive agent. The second active agent in the matrix may or may not bethe same as the first active agent in the plurality of microparticles.In certain embodiments, the matrix further comprises a second additive.In certain embodiments, the second additive may or may not be the sameas the first additive contained in the plurality of microparticles.

The weight percentages of the matrix in the controlled releasecomposition can vary in any suitable ranges. In certain embodiments, thecontrolled release composition comprises a weight percentage of 2% toabout 98% of the second material. In certain other embodiments, thecontrolled release composition comprises a weight percentage of 20% toabout 80% of the second material. In certain embodiments, the controlledrelease composition comprises a weight percentage of 0% to about 70% ofthe second active agent. In certain other embodiments, the controlledrelease composition comprises a weight percentage of 0% to about 30% ofthe second active agent. In certain embodiments, the controlled releasecomposition comprises a weight percentage of 0% to about 30% of thesecond additive. In certain other embodiments, the controlled releasecomposition comprise a weight percentage of 0% to about 20% of thesecond additive.

The plurality of microparticles can be operably linked to the matrix inthe controlled release composition. The term “operably linked” or“operably linking”, as used herein, includes embedding, incorporating,integrating, binding, combining, cross-linking, mixing, and/or coatingmicroparticles to a matrix. In certain embodiments, the microparticlescan be embedded in the matrix. In certain embodiments, themicroparticles can be uniformly or randomly distributed or embedded inthe matrix. In certain embodiments, the plurality of microparticles canbe distributed or embedded in the matrix in accordance with apre-determined pattern, such as, without limitation, a layered pattern.In certain embodiments, the matrix can be coated on the surface of themicroparticles. In certain embodiments, a portion of the microparticlescan be embedded within the matrix and the rest of the microparticles canbe coated on the surface of the matrix. A schematic drawing in FIG. 14shows a representative constitution of the controlled releasecomposition.

In certain embodiments, the controlled release composition furthercomprises a coating. A coating can be decided by a person skilled in theart as appropriate, for example, a coating can be desired to modify thephysiochemical properties of the controlled release composition (e.g.opacity) or to modify the release rate or release profile of the activeagent from the composition.

The shape and size of the plurality of microparticles and/or thecontrolled release composition can be selected as appropriate by aperson skilled in the art. The microparticles can be in any suitableshape known in the art, such as, without limitation, amorphous, tubular,platelet, granule, block, and membrane. The size of the plurality ofmicroparticles can vary in a wide range. In certain embodiments, atleast one of the plurality of microparticles has a size (diameter)ranging from about 1 μm to about 5000 μm. In certain embodiments, atleast one of the plurality of microparticles has a size (e.g. diameter)ranging from about 20 μm to about 1000 μm.

The controlled release composition can be of any irregular shapes orregular shapes, such as, without limitation, pellets, pellet chains,rings, patches, membranes, granules, balls, blocks, needles, andcylinders. In certain embodiments, the controlled release compositioncan be in the shape of cylinders, membranes, pellets, or pellet chains.

The controlled release composition can be of any size compatible withthe route of administration and the target site and can be selected asappropriate by a person skilled in the art. In certain embodiments, thecontrolled release composition can be of a size of about 0.2 mm to about200 mm. For example, the controlled release composition can be of acylinderical shape with a radius of about 0.2 mm to about 10 mm and alength of about 0.3 mm to about 20 mm, or a radius of about 0.3 mm toabout 5 mm and a length of about 0.4 mm to about 10 mm. For anotherexample, the controlled release composition can be of a membrane orpatch shape with a radius of about 5.0 mm to about 150 mm and athickness of about 0.1 mm to about 5 mm; a radius of about 10 mm toabout 60 mm and a thickness of about 0.3 mm to about 2 mm; a length ofabout 5.0 mm to about 150 mm, a width of about 3.0 mm to about 100 mm,and a thickness of about 0.1 mm to about 5 mm; or a length of about 10mm to about 100 mm, a width of about 5.0 mm to about 100 mm, and athickness of about 0.3 mm to about 2 mm. For yet another example, thecontrolled release composition can be of a granule shape with a radiusof about 0.5 mm to about 20 mm, or about 3.0 mm to about 10 mm.

In another aspect, the present disclosure provides a controlled releasecomposition comprising a plurality of microparticles operably linked toa matrix, wherein the controlled release composition can be formed inaccordance with the method comprising: preparing a plurality ofmicroparticles comprising a first material and a first active agent; andapplying the plurality of microparticles to a matrix-forming compositionthereby forming the controlled release composition.

II. Method of Preparation

In another aspect, the present disclosure provides a method for makingthe controlled release composition provided herein, comprising:preparing a plurality of microparticles comprising a first material anda first active agent; and applying the plurality of microparticles to amatrix-forming composition thereby forming the controlled releasecomposition.

The plurality of microparticles provided herein can be prepared by anysuitable methods known in the art. In certain embodiments, themicroparticles can be prepared by providing the first material to thefirst agent, and forming the microparticles. The first material can beone or more polymer(s), one or more non-polymeric organic compound(s),or a combination of one or more polymer(s) and one or more non-polymericorganic compound(s). In certain embodiments, the microparticles can beprepared by providing the polymer-forming monomers to the first agent,and forming the microparticles. The polymer-forming monomers can bepolymerized to form a polymer. In certain embodiments, the method ofpreparing the microparticles further comprises dividing the obtainedproduct into the microparticles of desirable sizes.

In certain embodiments, microparticles can be prepared by mixing activeagents, polymer-forming monomers, and optionally, additives andcatalysts, and cross-linking the polymer-forming monomers to form thepolymer, thereby entrapping the active agents within the polymer to formthe microparticles. Monomers and methods and conditions suitable forforming polymers suitable for the purposes of the present disclosure areknown in the art and can be selected by persons skilled in the artwithout undue experimentation. The polymerization conditions can bedetermined and adjusted as appropriate to form the polymer and themicroparticles by a person skilled in the art. For example, the firstactive agent can be mixed with methacrylate monomers, and the mixturecan be reacted in the presence of perbenzoic acid at 80° C. under normalatmospheric pressure to allow formation of poly(methacrylate)microparticles, which are incorporated with the first active agent.

Various methods known in the art can be used to prepare themicroparticles, including, for example, coacervation method such assingle coacervation and complex coacervation, emulsion solidification,solvent evaporation, solvent extraction, cross-linking method, hot-meltencapsulation, interfacial polymerization, spray drying, spray coating,fluid-bed coating, and pan coating, supercritical fluid method, doubleaxis extrusion, and centrifugation based method (for review, pleaserefer to: J. Swarbrick, Encyclopedia of pharmaceutical technology,Volume 4, Edition 3, published by Informa Health Care, 2007, p2316-2325; S. Benita, Microencapsulation: methods and industrialapplications, published by CRC Press, 2006, p 2-41). The methods ofpreparing microparticles can be selected by a person skilled in the artas appropriate, taking into consideration factors such as the desirablesize of the microparticles, the physiochemical characteristics of theactive agent and/or the first material, and the required equipments.

In one embodiment, microparticles can be prepared using aphysicochemical process. For example, microparticles can be prepared byreducing the solubility of the first material in the first materialsolution/composition through adding a flocculant. Microparticles canalso be prepared where materials with opposite charges are used as thecomposite materials, and the composite materials are cross-linked toencapsulate active agents into the resulting microparticles.Microparticles can also be prepared where a solvent capable of inducingphase separation is added into the first material composition/solution,causing the formation of microparticles. Microparticles can further beformed where the first material are melted or dissolved at a hightemperature and then cooled. In addition, microparticles can be preparedeliminating volatile solvents (such as, by evaporation) in thedispersion phase of an emulsion composition. Furthermore, microparticlescan be prepared by dissolving the first material and the first activeagent in a solvent, followed by eliminating the solvent and grinding theparticles formed.

In another embodiment, microparticles can be prepared using a physicalmechanical process. For example, microparticles can be prepared using aspray drying process which involves applying the first active agent intothe first material solution, followed by atomizing the mixture into hotinertia airflow. Droplets are formed, condensed, and dried to formmicroparticles. Microparticles can also be formed by using a spraycooling process where the first active agent and the first materialcomposition (e.g., a melted first material composition comprising thefirst active agent) is sprayed into a cooled airflow, resulting in theformation of microparticles. Microparticles can further be formed usinga centrifugation-based process, a fluid bed coating-based process, or asupercritical fluid-based process. In addition, microparticles can beprepared using extrusion or a pan coating process, where the formerinvolves blending the first active agent and the first material in anextruder, followed by kneading and grinding to form microparticles, andthe later involves coating drug particles with materials.

In yet another embodiment, microparticles can be prepared using achemical process. For example, microparticles can be prepared using aninterfacial polycondensation process which involves a polycondensationreaction which occurs at the interface of a dispersed phase (e.g.,water) and a continuous phase (e.g., organic phase). Microparticles canalso be formed by using a radiation-based cross-linking process.

In still another embodiment, microparticles can be prepared using amelting process. For example, the first material, the first activeagent, and optionally, additives can be mixed, and the mixture can bemelted, cooled, and grinded to form microparticles. Microparticles canalso be formed when melted first active agent and the first materialmixture is added into a blender and cooled while being activelyagitated. Microparticles can also be formed where melted first activeagent and the first material mixture is applied onto the surface of asubstrate (e.g., stainless steel) and rapidly cooled, and the resultingsolids are crashed/grinded.

In certain embodiments, the prepared microparticles can be furthercoated, such as, without limitation, by using a pan coating process, ora fluid bed coating process (for review, please refer to: J. Swarbrick,Encyclopedia of pharmaceutical technology, Volume 4, Edition 3,published by Informa Health Care, 2007, p 2330-2331). For example, acoating can be desirable for making a controlled release compositionhaving a release period of months or years.

The controlled release composition can be prepared by applying theplurality of microparticles to a matrix-forming composition. As usedherein, the term “matrix-forming composition” refers to a compositioncomprising substances for forming a matrix, which includes, withoutlimitation, the second material, a polymer, polymer-forming monomers, anon-polymeric organic compound, active agents, additives, catalysts,solvent, and/or combinations thereof. In certain embodiments, the methodfurther comprises mixing the plurality of microparticles with amatrix-forming composition.

In certain embodiments, the matrix-forming composition comprisesmonomers for forming a polymer. In certain embodiments, the controlledrelease composition can be prepared by mixing the microparticles,polymer-forming monomers, and optionally, active agents, additives, andcatalysts, and cross-linking the polymer-forming monomers to form thepolymer, thereby entrapping the microparticles within the polymernetwork to form the matrix operably linked to the microparticles.Monomers, methods and conditions suitable for forming the polymer of thepresent disclosure can be selected by a person skilled in the artwithout undue experimentation.

In certain embodiments, the matrix-forming composition comprises thesecond material. The second material can be a polymer, a non-polymericorganic compound, or a combination of a polymer and a non-polymericorganic compounds. In certain embodiments, the controlled releasecomposition can be prepared by mixing the microparticles, the secondmaterial, and forming the controlled release composition.

The controlled release composition can be prepared from themicroparticles and the matrix-forming composition by any suitabletechniques known in the art. Exemplary techniques include, withoutlimitation, extrusion, extrusion moulding, injection molding,compression moulding, casting, coating, calendering and the like.

Extrusion method involves pushing or drawing the microparticles and thematrix-forming composition through a die of a desired cross-section. Theextrusion process can be performed using an extruder such as a screwextruder, a sieve and basket extruder, a roll extruder and a ramextruder.

Extrusion moulding method involves extruding the microparticles and thematrix-forming composition and feeding the resulting material into a dieto form a certain shape.

Injection molding method involves feeding the microparticles and thematrix-forming composition into a container and forcing them into a moldcavity.

Compression molding method involves placing microparticles and thematrix-forming composition in an open mold cavity, and applying pressureto the closed mold to force the material into contact with all moldareas.

Casting method involves pouring the microparticles and thematrix-forming composition into a mold cavity, and allowing the materialto solidify. In certain embodiments, casting process can be preferredwhen making a controlled release composition having the shape of a patchor membrane.

Coating method involves applying a layer of matrix-forming compositionon the surface of the microparticles.

Calendering method involves extruding the microparticles and thematrix-forming composition and forcing the resulting material to passunder rollers to take shape.

In certain embodiments, the method further comprises providing the shapefor the controlled release composition. The shape of the controlledrelease composition can be of any irregular shapes or regular shapes,such as, without limitation, pellets, pellet chains, rings, patches,membranes, granules, balls, blocks, needles, and cylinders. Any suitablemethods for providing shapes can be used. For example, the controlledrelease composition can be loaded to a syringe and pushed to passthrough a needle to form cylindrical shaped controlled releasecomposition.

In certain embodiments, the method of preparing the controlled releasecomposition further comprises heating the microparticles and thematrix-forming composition to a predetermined temperature T_(m), whereT_(H)>T_(m)>T_(L). It is desirable that at temperature T_(m), the matrixforming composition is liquefied while the microparticles do notliquefy, and the liquefaction of the matrix forming composition can bereversed when cooled down. It is also desirable that at temperatureT_(m), the matrix forming composition does not decompose. If T_(L) isthe decomposition temperature of the second material, or if T_(L)exceeds the decomposition temperature of one component of the secondmaterial, the controlled release composition can be prepared usingmethods other than heating the microparticles and the matrix-formingcomposition to a predetermined temperature T_(m).

The temperature T_(m) used in various embodiments of the presentdisclosure can be selected by a person skilled in the art without undueexperimentation. For example, T_(m) can be determined using the formula:(T_(H)+T_(L))/2. In one embodiment, T_(m) can be a temperature in arange of (T_(H)+T_(L))/2±about 5° C., (T_(H)+T_(L))/2±about 10° C.,(T_(H)+T_(L))/2±about 15° C., or (T_(H)+T_(L))/2±about 20° C. In anotherembodiment, T_(m) can be determined using the formula: T_(H)−T_(m) about5° C., T_(H)−T_(m) about 10° C., T_(H)−T_(m) about 15° C., orT_(H)−T_(m) about 20° C. In yet another embodiment, T_(m) can bedetermined using the formula: T_(m)−T_(L) about 5° C., T_(m)−T_(L)≧about10° C., T_(m)−T_(L) about 15° C., or T_(m)−T_(L) about 20° C. In stillanother embodiment, T_(m) can be in a range from (T_(L)+about 5° C.) to(T_(H)−about 5° C.), from (T_(L)+about 10° C.) to (T_(H)−about 10° C.),from (T_(L)+about 15° C.) to (T_(H)−about 15° C.), from (T_(L)+about 20°C.) to (T_(H)−about 20° C.).

In certain embodiments, when the plurality of microparticles comprise acoating, the T_(m) can be further selected to be below the initialmelting temperature of the coating substance of the microparticles.

In certain embodiments, the method of preparing the controlled releasecomposition further comprises dissolving the matrix-forming compositionin a solvent. The solvent can be selected where the first material orthe microparticles comprising the first material are insoluble orsubstantially insoluble in such solvent. In certain embodiments, thesolvent can be evaporated to form the controlled release composition.

III. Method of Use

In another aspect, the present disclosure provides a method of treatingand/or preventing a condition in a subject, comprising administering tothe subject the controlled release composition provided herein.

The term “condition,” as used herein, includes, without limitation, apathological condition, a physiological condition, and a cosmeticcondition. In certain embodiments, a condition, such as an aging-relatedcondition, simultaneously be a pathological condition, a physiologicalcondition, and a cosmetic condition.

Examples of pathological condition include without limitation, aging,angina, antithrombin deficiency, arrhythmia, atherosclerosis, artrialfibrillation, atrial flutter, blood clots, cardiacischemia, cardiacsurgery, cardiomyopathy, cardiovascular abnormalities, carotid arterydisease, chest pain, circulation disorders, claudication, collagenvascular diseases, congenital heart diseases, congestive heart failure,coronary artery disease, diabetes, diabetes and hypertension,dyslipidemia, dysrhythmia, elevated triglycerides, heart defect, heartdisease, heart failure, heart valve disease, hemangioma, highcholesterol, hypertriglyceridemia, intermittent claudication,hypertension, Kawasaki disease, heart attack, myocardial ischemia,orthostatic hypotension, peripheral arterial disease, peripheralarterial occlusive disease, peripheral vascular disease, Raynaud'sdisease, smoking cessation, tachycardia (fast heart rate), thrombosis,varicose veins, vascular diseases, venous leg ulcers, gingivitis, gumdiseases, halitosis, oral cancer, periodontal disease, temporomandibulardisorders, temporomandibular joint syndrome, sunburn, acne, skin aging,alopecia, anesthesia, athlete's foot, atopic dermatitis, bed sores(decubitus ulcers), bunions, burns, burn infections, cold sores (herpeslabialis infections), congenital skin diseases, contact dermatitis,cutaneous lupus erythematosus, diabetic foot ulcers, eczema, excessivesweating, fabry disease, fungal infections, genital herpes, genitalwarts, hair loss, hair removal, hand dermatitis, head lice, hemangioma,hereditary angioedema, herpes simplex infections, herpes Zosterinfections, herpetic neuralgia, hives, ichthyosis, ischemic foot ulcers,keratoses, lupus, male pattern baldness, malignant melanoma, medicalprosthetics, melanoma, molluscum contagiosum, mycosis fungoides,onychomycosis, pemphigus vulgaris, postherpetic neuralgia, pressureulcers, psoriasis and psoriatic disorders, psoriatic arthritis, razorbumps, rosacea, sarcoidosis, scalp disorders, scar tissue, scleroderma,seborrhea, seborrheic dermatitis, shingles, skin cancer, skininfections, skin lipomas, skin wounds, solar lentigines, sporotrichosis,staphylococcai skin infections, stasis dermatitis, stretch marks,systemic fungai infections, sun poisoning, ringworm, tinea capitis,tinea versicolor, urticaria, vitiligo, warts, wounds, acromegaly,adrenal cancer, congenital adrenal hyperplasia, diabetes mellitus (typeI and type II), diabetes mellitus (type I), diabetes mellitus (type II),diabetic gastroparesis, diabetic kidney disease, diabetic macular edema,diabetic neuropathy, diabetic retinopathy, diabetic vitreous hemorrhage,dyslipidemia, female hormonal deficiencies/abnormalities, Fredricksontype III. hyperlipoproteinemia, growth hormonedeficiencies/abnormalities, gynecomastia, hair removal, hyperlipidemia,hormone deficiencies, hot flash, hyperparathyroidism, idiopathic shortstature, indication: diabetes type II, male hormonaldeficiencies/abnormalities, McCune-Albright syndrome, menopausedisorders, metabolic syndrome, obesity, ovarian cancer, pancreaticcancer, pancreatic disorders, pancreatitis, parathyroid cancer,parathyroid disease, parathyroid disorders, perimenopause, pituitarydisorders, polycystic ovarian syndrome, post menopause disorders, postmenopause osteopenia, precocious puberty, primary insulinhypersecretion, severe short stature, sexual dysfunction, thyroiddisease, thyroid disorders, Turner syndrome, Wilms' tumor, Wilson'sdisease, abdominal cancer, achalasia, alpha 1 antitrypsin deficiency,anal fissures, appendicitis, Barrett's esophagus, biliary tract cancer,bowel dysfunction, celiac disease, chronic diarrhea, clostridiumdifficile-associated diarrhea, colon cancer, colon polyps, colorectalcancer, constipation, Crohn's disease, diabetic gastroparesis, digestivesystem neoplasms, duodenal ulcers, Fabry disease, fecal incontinence,functional dyspepsia, gall bladder disorders, gastric cancer, gastriculcers, gastroenteritis, gastroesophageal reflux disease,gastrointestinal disease and disorders, gastroparesis, heartburn,helicobacter pylori, hemorrhoids, hepatic encephalopathy, hepatitis,ileus, infectious colitis, inflammatory bowel disease, intra-abdominalinfections, irritable bowel syndrome, liver disease, liver disorders,non-erosive reflux disease, non-ulcer dyspepsia, organ rejectionfollowing organ transplantation, post-operative nausea and vomiting,vomiting, rectal cancer, rectal disorders, recurrent diarrhea, stomachcancer, stomach discomfort, ulcerative colitis, abnormal blood vessels,acute myelogenous leukemia, anemia, anemia (non-Hodgking lymphoma),non-small-cell lung cancer, anemic cancer, aneurysm, antiphospholipidsyndrome, antithrombin deficiency, aplastic anemia, blood clots,candidemia/candidiasis, chronic renal anemia, Gaucher disease,hematologic cancer, hematological disorders, paroxysmal hemoglobinuria,hemorrhages, hypercalcemia, hypogammaglobulinemia, hyponatremia,idiopathic thrombocytopenic purpura, islet cell cancer, leukemia, B-celllymphoma, lymphomas, multiple myelomas, myelodysplastic syndromes,myocardial ischemia, occlusions, platelet deficiencies, plateletdisorders, red cell disorders, renal anemia, sezary syndrome, sicklecell disease, T-cell lymphoma, thalassemia, thrombocytopenia, vonWillebrand's disease, white cell disorders, acquired immune deficiencysyndrome (AIDS), AIDS related infections, acute rhinitis, allergies,asthma, anal dysplasia, bacterial infections, canker sores, celiacdisease, cervical dysplasia, chickenpox, chronic fatigue syndrome,common cold, common variable immunodeficiency, bacterial conjunctivitis,chronic obstructive pulmonary disease, cutaneous candidiasis, cutaneousT-cell lymphoma, cytomegalovirus infections, dermatomyositis, fever,graft-versus-host disease, hepatitis, hepatitis B, hepatitis C, HIVinfections, HIV/AIDS, human papilloma virus infections,hypogammaglobulinemia, idiopathic inflammatory myopathies, influenza,intra-abdominal infections, Kaposi's sarcoma, lupus, lyme tick disease,mycobacterium avium complex infection, meningitis, onychomycosis, oralcandidiasis, pneumonia, polymyositis (inflammatory muscle disease),postherpetic neuralgia, primary immunodeficiency disorders, respiratorysyncytial virus infection, rheumatic fever, allergic rhinitis, rotavirusinfection, sarcoidosis, sepsis and septicemia, sexually transmitteddiseases, shingles, Sjogren's syndrome, smallpox, soft tissueinfections, staphylococcal infections, staphylococcal skin infections,strep throat, systemic candidiasis, systemic lupus erythematosus, throatand tonsil infections, urticaria, vancomycin resistant enterococci, westnile virus infections, acromegaly, ankylosing spondylitis, bone loss,athletic injuries, bone diseases, bone metastases, breast pain, bunions,bursitis, carpal tunnel syndrome, cartilage injuries, chest pain,chronic back pain, chronic leg pain, chronic pain, chronic shoulderpain, claudication, congenital lactic acidosis, connective tissuediseases, dermatomyositis, dupurtren's disease, fibromyalgia, Frozenshoulder, adhesive capsulitis, gout (hyperuricemia), idiopathicinflammatory myopathies, intermittent claudication, joint injuries, kneeinjuries, multiple sclerosis, muscle pain, muscular dystrophy,musculoskeletal diseases, myasthenia gravis (chronic weakness),myasthenia gravis generalized, orthopedics, osteoarthritis,osteomyelitis, osteoporosis, osteosarcoma, Paget's disease, partialmedial meniscectomy, parathyroid disease, post-menopausal osteopenia,post-menopausal osteoporosis, reflex sympathetic dystrophy syndrome,rheumatoid arthritis, sciatica, spinal cord disorders, spinal cordmalignancy, spine athroplasty, sprains, tendon injuries, tennis elbow,tic disorders, anal dysplasia, benign prostatic hyperplasia, bladdercancer, bladder disorders, blood cancers, catheter complications,chronic pelvic pain, diabetic kidney disease, enuresis, erectiledysfunction, fabry disease, nocturia, genitourinary prolapse,glomerulonephritis, glomerulosclerosis, idiopathic membranousnephropathy, impotence, interstitial cystitis, kidney cancer, kidneydisease, kidney failure, kidney stones, liver cancer, low testosterone,mastectomy, medical prosthetics, nephropathy, Peyronie's disease,premature ejaculation, prostate cancer, prostate disorders, prostaticintraepithelial neoplasia, proteinuria, Reiter's syndrome, renal arterydisease, renal cell carcinoma, renal failure, testicular cancer,tyrosinemia, urethral strictures, urinary incontinence, urinary tractinfections, urothelial tract cancer, male erectile dysfunction andfemale sex dysfunction, systemic blood pressure, abortion, hypotensivecontrol, inhibition of platelet aggregation, pulmonary diseases,gastrointestinal disease, inflammation, shock, reproduction, fertility,bone loss, bone fractures, osteoporosis, metastatic bone disease,Paget's disease, periodontal disease, cartilage degeneration,endometriosis, uterine fibroid disease, hot flashes, increased levels ofLDL cholesterol, cardiovascular disease, impairment of cognitivefunctioning, cerebral degenerative disorders, restenosis, gynecomastia,vascular smooth muscle cell proliferation, obesity, incontinence,anxiety, depression resulting from an estrogen deficiency,perimenopausal depression, post-partum depression, premenstrualsyndrome, manic depression, anxiety, dementia, obsessive compulsivebehavior, attention deficit disorder, sleep disorders, irritability,impulsivity, immune deficiency, auto immune diseases, anger management,multiple sclerosis and Parkinson's disease, inflammation, inflammatorycondition, inflammatory bowel disease, respiratory diseases, sexualdysfunction, hypertension, retinal degeneration, asthma, cancers,rheumatoid arthritis, chronic inflammatory disorders, diabetes, chronicpain, central nerves system diseases, cardiovascular diseases, renaldisease, reproductive diseases, infections, epilepsy, microcirculationimprovement, drug withdrawal syndrome, bone marrow disease, edema, or apathological condition related to a position in a subject (e.g., ahuman, an animal) which could be reached by an endoscope.

In certain embodiments, the pathological condition can be a cancerouscondition. Cancerous conditions and tumor types that can be treatedusing the controlled release composition disclosed herein include butare not limited to carcinoma, blastoma, sarcoma, germ cell tumor, orhematological or lymphoid malignancy such as leukemia, lymphoma, ormultiple myeloma. More specifically, cancerous conditions and tumortypes that can be treated using the controlled release compositiondisclosed herein include but are not limited to squamous cell cancer,lung cancer (e.g., small cell lung cancer, non-small cell lung cancer(NSCLC), adenocarcinoma of the lung, or squamous cell carcinoma of thelung), cancer of the peritoneum, liver cancer (e.g., hepatocellularcarcinoma/hepatoma), gastric or stomach cancer (e.g., gastrointestinalcancer), pancreatic cancer, brain tumor (e.g., glioblastoma/glioblastomamultiforme (GBM), non-glioblastoma brain tumor, or meningioma), glioma(e.g., ependymoma, astrocytoma, anaplastic astrocytoma,oligodendroglioma, or mixed glioma such as oligoastrocytoma), cervicalcancer, ovarian cancer, uterine cervix cancer, liver cancer (e.g.,hepatoblastoma, hepatocellular carcinoma/hepatoma, or hepaticcarcinoma), bladder cancer (e.g., urothelial cancer), breast cancer,colon cancer, colorectal cancer, rectal cancer, endometrial or uterinecarcinoma, salivary gland carcinoma, esophageal carcinoma, kidney orrenal cancer (e.g., rhabdoid tumor of the kidney), prostate cancer,vulval cancer, penile cancer, anal cancer (e.g., anal squamous cellcarcinoma), thyroid cancer, parathyroid carcinoma, head and neck cancer(e.g., nasopharyngeal cancer, corpus linguae tumor, gingival neoplasm,and tonsillar tumor), skin cancer (e.g., melanoma or squamous cellcarcinoma), osteosarcoma, osteocarcinoma, osteoma sarcomatosum, Ewing'ssarcoma, chondrosarcoma, soft tissue sarcoma (e.g., rhabdomyosarcoma,fibrosarcoma, Kaposi's sarcoma), carcinoid cancer, eye cancer (e.g.,retinoblastoma), mesothelioma, lymphocytic/lymphoblastic leukemia (e.g.,acute lymphocytic/lymphoblastic leukemia (ALL) of both T-cell lineageand B-cell precursor lineage, chronic lymphoblastic/lymphocytic leukemia(CLL), acute myelogenous/myeloblastic leukemia (AML), including mastcell leukemia, chronic myelogenous/myelocytic/myeloblastic leukemia(CML), hairy cell leukemia (HCL), Hodgkin's disease, non-Hodgkin'slymphoma, chronic myelomonocytic leukemia (CMML), follicular lymphoma(FL), diffuse large B cell lymphoma (DLCL), mantle cell lymphoma (MCL),Burkitt's lymphoma (BL), mycosis fungoides, Sezary syndrome, cutaneousT-cell lymphoma, mast cell neoplasm, medulloblastoma, nephroblastoma,solitary plasmacytoma, myelodysplastic syndrome, chronic and non-chronicmyeloproliferative disorder, central nervous system tumor, pituitaryadenoma, vestibular schwannoma, primitive neuroectodermal tumor,ependymoma, choroid plexus papilloma, polycythemia vera,thrombocythemia, idiopathic myelfibrosis, and pediatric cancers such aspediatric sarcomas (e.g., neuroblastoma, rhabdomyosarcoma, andosteosarcoma). In addition, tumors can be malignant (e.g., cancers) orbenign (e.g., hyperplasia, cyst, pseudocyst, hamartoma, and benignneoplasm).

Examples of physiological conditions include without limitation, aging,contraception, wound healing, and post surgical adhesion.

Examples of cosmetic condition include without limitation, skin aging(e.g. wrinkling, loss of elasticity, sagging, uneven pigmentation, andloss of underlying tissue mass), cosmetic defect (e.g. striaegravidoram, striae distensiae, atrophic scarring, wound or surgicalscarring, or hair loss), undesired pigmentation, or post-cosmeticprocedure damage resulted from, for example, chemical peel,dermabrasion, laser resurfacing, ablative resurfacing, nonablativeresurfacing, photodynamic therapy, noncoherent light phototherapy,breast lift, face lift, eyelid lift, forehead lift, neck lift, thighlift, buttock lift, tummy tuck, and scar revision.

The controlled release composition disclosed herein can be administeredto a target site via any suitable methods. The term “target site” refersto the site in a living organism where a condition occurs. By deliveringthe controlled release composition to the target site, the active agentcontained in the controlled release composition can be released in acontrolled fashion in proximity of the target site, and acts toalleviate or treat the condition. In certain embodiments, the controlledrelease composition can be surgically implanted, injected, administeredvia percutaneous puncture, introduced through a body opening, ortopically applied to a target site.

In certain embodiments, the controlled release composition can besurgically implanted to the target site. For example, in an opensurgery, the controlled release composition can be spread by hand or beplaced by a device such as forceps or the like to a tissue in need suchas brain or kidney. For another example, the controlled releasecomposition can be injected via a specialized needle into a target sitesuch as a solid tumor during surgery. For yet another example, thecontrolled release composition can be inserted into a cavity or anincision during a surgery. In certain embodiments, the controlledrelease composition can be further fixed to the target site, forexample, with protein-based glue, or biodegradable gauze.

In certain embodiments, the controlled release composition can beinjected to the target site. The injection can be performed using asyringe and a needle. The controlled release composition can be injectedto the target site via any suitable routes such as subcutaneous,intraperitoneal, intramuscular, intradermal, intranasal, or intraocularinjection. For example, the pellet shaped controlled release compositioncan be injected into muscle tissues. For another example, the controlledrelease composition suitable for injection can be injectedsubcutaneously.

In certain embodiments, the controlled release composition can beadministered via percutaneous puncture. The puncture needle can beguided to the target site by using imaging techniques such asultrasound, fluoroscopy, computed tomography (CT) or laser. Once thepuncture needle reaches the target site, the controlled releasecomposition can be delivered via the needle. The puncture route can bestraight forward to the target site, and should avoid disruption ofnerves or blood vessels. The controlled release composition can beadministered via percutaneous puncture to any suitable target site, suchas for example, kidney, lung and lumbar.

In certain embodiments, the controlled release composition can beintroduced through a body opening. The body opening can be a naturalbody opening such as mouth, or can be an incision in a body cavity suchas an incision in chest or abdomen. In certain embodiments, thecontrolled release composition can be inserted into a target sitedirectly through the body opening. For example, the controlled releasecomposition can be inserted into a cavity such as the periodontal, oral,vaginal, rectal or nasal cavity, a pocket such as a periodontal pocketor the eye, with or without creating an incision at the site. In certainembodiments, the controlled release composition can be delivered to thetarget site by hand. In certain embodiments, the controlled releasecomposition can be delivered to the target site by an applicator. Anapplicator can be used when it is difficult to deliver the controlledrelease composition to the target site by hand, or when it is notconvenient to place a uniform layer of the controlled releasecomposition at the target site. Any suitable applicator can be used. Forexample, an applicator can be loaded with the controlled releasecomposition in one end and operable to release the composition at theother end. In certain embodiments, the controlled release compositioncan be placed on the surface of an implantable device, such as a stent,and the implantable device can be placed to the target site to allowdelivery of the controlled release composition. For example, thecontrolled release composition can be placed on the surface of anesophageal stent which is then placed at the diseased site of theesophagus. In certain embodiments, the controlled release compositioncan be introduced through a body opening via a delivery device. Suitabledelivery device includes, for example, endoscope, delivery catheter, asurgically placed drain or access port or other applicators such as aneedle. The delivery device can be introduced through a body opening andprovide an access route to the target site to allow delivery of thecontrolled release composition to the particular site. In certainembodiments, the delivery device can be used in combination. Forexample, endoscope and implantation needle can be used in combination toallow introduction of the controlled release composition inside acancerous tissue in pancreatic gland. The controlled release compositioncan be delivered via a delivery device to a body tract, cavity, ororgan, such as for example, gastrointestinal tract (e.g. esophagus,stomach and duodenum, small intestine, large intestine, colon, bileduct, rectum), respiratory tract (e.g. nose, lower respiratory tract),ear tract, urinary tract, female reproductive system (e.g. cervix,uterus, fallopian tubes), abdominal or pelvic cavity, eye, interior of ajoint, heart, lung, amnion, fetus, breast, and spine.

In certain embodiments, the controlled release composition can betopically applied to a target site. For example, the controlled releasecomposition can be applied to the surface with or without fixation, forexample without limitation, with glue or gauze. For another example, thecontrolled release composition can be dripped or brushed on the surfaceof the target site.

The controlled release composition can be administered to a subject at adosage and for a release period. The dosage of the controlled releasecomposition can be selected or adjusted by a person skilled in the artas sufficient for release of the active agent for a selected releaseperiod.

In certain embodiments, the dosage of the controlled release compositioncan be sufficient for release of a therapeutically effective amount ofthe active agent for the selected release period. The term“therapeutically effective amount” refers to the concentration of theactive agent at the target site or in the blood, which concentration iseffective to treat or prevent the target condition yet to allow thesubject to tolerate such concentration without showing significantadverse effects. The therapeutically effective amount will depend onvarious factors known in the art, such as for example extent of thecondition, the effect desired, state of health of the subject, potentialfor cross-reaction, allergies, sensitivities and adverse side-effects,past medical history, present medications, body weight and age.

In certain embodiments, the released amount of the active agent from thecontrolled release composition can be significantly less than (e.g. 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% less than) the clinicallyapproved dosage for systemic administration for the same period, whilereaching similar local concentration. For example, the controlledrelease composition loaded with 5 clinically approved daily dosages forsystemic administration can be sufficient for a release period of 10days while achieving similar local concentrations and similar clinicaleffects. For another example, the controlled release compositionadministered at a dosage of 5 mg/kg (in terms of active agent) for arelease period of two weeks can achieve a tumor inhibition rate of 20%,while systemic administration of the active agent at a dosage of 12mg/kg for four consecutive doses in two weeks achieved a tumorinhibition rate of 19%.

In certain embodiments, the released amount of the active agent from thecontrolled release composition can be significantly less than (e.g. 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% less than) the clinicallyapproved dosage for systemic administration for the same period, whileachieving even better local concentrations and better clinical outcome.For example, the controlled release composition administered at a dosageof 10 mg/kg (in terms of active agent) for a release period of two weekscan achieve a tumor inhibition rate of 37%, while systemicadministration of the active agent at a dosage of 12 mg/kg for fourconsecutive dosages in two weeks achieved a tumor inhibition rate of19%.

The release rate of the active agent from the controlled releasecomposition can be varied due to different material properties, such asthe type of the materials, the molecular weight of the materials, themolar fraction ratio of the monomers in a copolymer, the percentage of acertain material in the composition, and etc. The release of the activeagent can last over a prolonged duration of time equal to or greaterthan about 1 day up to about 10 years after administration, for example,from about 1 day to about 5 years after administration, from about 1 dayto about 2 years after administration, from about 1 day to about 2 yearsafter administration, from about 1 day to about 1 year afteradministration, from about 1 day to about 6 months after administration,from about 1 day to about 3 months after administration, from about 1day to about 1 month after administration, from about 1 day to about 2weeks after administration, from about 1 day to about 1 week afteradministration, from about 1 day to about 5 days after administration,from about 1 month to about 2 years after administration, from about 2months to about 2 years after administration, from about 3 months toabout 2 years after administration, from about 6 months to about 2 yearsafter administration, and from about 1 year to about 2 years afteradministration.

The release of the active agent from the controlled release compositioncan be in a time-dependent manner. In certain embodiments, thecontrolled release composition releases, in the first 3 days afteradministration, about less than 85% of the total amount of the activeagent, about less than 80% of the total amount of the active agent,about less than 70% of the total amount of the active agent, about lessthan 60% of the total amount of the active agent, about less than 50% ofthe total amount of the active agent, about less than 40% of the totalamount of the active agent, or about less than 30% of the total amountof the active agent. In certain embodiments, the controlled releasecomposition releases, in the first 10 days after administration, aboutless than 75% of the total amount of the active agent, about less than70% of the total amount of the active agent, about less than 65% of thetotal amount of the active agent, about less than 60% of the totalamount of the active agent, about less than 55% of the total amount ofthe active agent, about less than 50% of the total amount of the activeagent, about less than 45% of the total amount of the active agent,about less than 40% of the total amount of the active agent, about lessthan 35% of the total amount of the active agent, or about less than 30%of the total amount of the active agent.

Without being bound by theory, it is believed that the release of theactive agent can be achieved by erosion and/or swelling of thematerial(s), and diffusion of the active agent from the microparticlesand/or from the matrix to the target tissue. The release of the activeagent can be influenced by factors such as the weight percentage ofmicroparticles, the size and shape of the microparticles, the size andshape of the controlled release composition, the physiochemicalproperties of the active agent, and the erosion and/or swelling rate ofthe materials. These factors can be adjusted and/or selected to suit thepurpose of treatment.

In certain embodiments, the weight percentage of the plurality ofmicroparticles in the controlled release composition can be selectedbased on the purpose of treatment and/or the biological system's needs.For example, controlled release composition with a relatively higherpercentage of microparticles can be used in treatment of variousdiseases. For another example, controlled release composition with arelatively lower percentage of microparticles can be used inanti-adhesion treatment during surgical operation, or can be used forsustained delivery of low-dose active agents such as hormones.

In certain embodiments, the size of the microparticles can be selectedbased on factors such as the release profile intended to achieve, thephysiochemical properties of the first active agent, and the particularpurpose of treatment. For example, microparticles with a diameterranging from about 50 μm to about 150 μm can be used to prepare acontrolled release composition designed for less than 10-day releaseperiod. For another example, microparticles with a diameter ranging fromabout 120 μm to about 1000 μm can be used to prepare a controlledrelease composition designed for more than 10-day release period. Foryet another example, microparticles with a diameter ranging from about50 μm to about 150 μm can be used to prepare a controlled releasecomposition containing a hydrophobic drug as the first active agentdesigned for more than 10-day release period. For still another example,microparticles with a diameter ranging from about 50 μm to about 150 μmcan be used to prepare a controlled release composition designed foranti-adhesion treatment during surgical operation.

The suitable shape of the controlled release composition can be selectedbased on factors such as the desired route of administration, purpose oftreatment, and ease of handling. For example, the cylinder shapedcontrolled release composition can be suitable for administering drugthrough percutaneous puncture or endoscopy, or during operation. Foranother example, the patch shaped controlled release composition can besuitable for prevention of post surgery adhesion. For yet anotherexample, the ball shaped controlled release composition can be suitablefor use in induction.

In certain embodiments, the controlled release composition can beadministered at a suitable frequency, such as for example, once a week,twice every three weeks, once every month, once every two months, onceevery six month, once a year, and once every two years.

ADVANTAGES

The controlled release compositions disclosed herein provide a varietyof desired properties. As a controlled release formulation, thecomposition provided herein offers clinical or practical advantages overthe conventional dosage forms. In certain embodiments, controlledrelease composition provided herein can be administered in asignificantly lower dosing frequency. The release period of the activeagent in the controlled release compositions reaches weeks, months oreven years, and thus reduce the necessity of frequent dosing and improvepatient's compliance. In certain embodiments, the controlled releasecompositions maintain a steady concentration of the active agent for aprolonged time, and achieve a more uniform pharmacological response.

In certain embodiments, the controlled release compositions can beadministered locally where a condition occurs without the necessity of asystematic administration. A local administration of a controlledrelease composition allows an active agent to reach the same level oflocal concentration with a much lower dosage than that required insystematic administration of the active agent. In addition, localadministration of the composition achieves a higher level of localconcentration which can not be afforded in the systematicadministration, or if possible, requires significantly higher dosage ofthe active agent in the systematic administration. The high localconcentration of the active agent enables the treatment of a conditionmore effectively or much faster than a systematically delivered activeagent and the treatment of new conditions that can not be possible orobserved before. In the meantime, local administration of the controlledrelease composition can have significantly lower systemic exposure ofthe active agents than systemic administration has, and therefore canreduce potential sufferings from a systemic administration, for example,adverse reactions associated with the systematic exposure to the activeagent, and/or gastrointestinal/renal effects.

In certain embodiment, the controlled release composition containsbiodegradable materials which biodegrades in vivo and thus does not needto be surgically removed after the depletion of the active agent in thecomposition. The biodegradable materials breaks down or degrades intonon-toxic components in vivo, without causing harm to the body.

In certain embodiments, when locally administered, the controlledrelease composition can be easily taken out from the subject after aperiod of time. This enables adjustment of dosage during treatment so asto better fit the physical state of the subject. The sample taken outfrom the subject also enables the measurement of the release curve, theinvestigation of the pharmacokinetic properties of the controlledrelease composition, and the generation of data required to obtainregulatory approval of the use of the controlled release composition.

In addition, compared to traditional microparticle-based controlledrelease compositions, the controlled release compositions of the presentdisclosure have a variety of improved physical, chemical, and/orpharmaceutical properties, e.g., without limitation, are more stable,have longer shelf life, require no solvent reconstitution, and are lessprone to leaking when implanted (such as, when implanted into a solidtumor).

The present disclosure is described in the following Examples, which areset forth to aid in the understanding of the invention, and should notbe construed to limit in any way the scope of the invention as definedin the claims which follow thereafter.

EXAMPLES Example 1

Preparation of fluorouracil microparticles: 6.0 g fluorouracil and 4.0 gpoly(L-lactic acid) (MW 20,000; melting range 162-168° C.) were mixedand melted at 170° C. The melted mixture was cooled and the resultingsolid was grinded to yield the fluorouracil microparticles (size: about180 μm).

Preparation of fluorouracil implants: 20.0 g poly (L-lactic-glycolicacid) (75/25; MW 16,000; melting range 68-76° C.), 12.0 g fluorouracil,and 8.0 g fluorouracil microparticles were mixed and extruded at 110° C.Cylindrical granules about φ 0.9 mm×4 mm in size were prepared(fluorouracil content: 42.0%).

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One fluorouracil implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 3. In vivo cumulative release of fluorouracil by the implantswas measured. And the results are as shown in Table 3.

TABLE 3 Time 1 day 5 days 15 days 30 days 50 days Cumulative release11.6% 37.3% 60.4% 74.1% 93.3% (%) RSD % 42.0% 26.6% 18.8% 11.1% 16.4%

Example 2

Preparation of fluorouracil microparticles: 6.0 g fluorouracil, 3.0 gpoly (L-lactic acid) (MW 20,000; melting range 162-168° C.), and 1.0 gdextran (40) were mixed and melted at 170° C. The melted mixture wascooled and the resulting materials were grinded to yield thefluorouracil microparticles (size: about 180 μm).

Preparation of fluorouracil implants: 17.0 g poly (L-lactic-glycolicacid) (75/25; MW 16,000; melting range 68-76° C.), 3.0 g polyethyleneglycol, 12.0 g fluorouracil, and 8.0 g fluorouracil microparticles wereblended. Cylindrical granules about φ 0.9 mm×4 mm in size were preparedby injection molding at 110° C. Fluorouracil content in the implants was42.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. 1-2 pieces of fluorouracil implants were implanted into themedial hind leg muscle of each mouse. Samples were collected at timepoints as indicated in Table 4. In vivo cumulative release offluorouracil by the implants was measured. And the results are as shownin Table 4.

TABLE 4 Time 1 day 5 days 10 days 15 days 20 days Cumulative release26.8% 52.4% 69.1% 80.3% 92.8% (%) RSD % 30.5% 18.8% 22.3% 13.0%  9.7%

Example 3

Preparation of etoposide microparticles: 6.0 g dextran (40) wasdissolved in 75% ethanol, followed by the addition of 10.0 g etoposideto create a mixture. Ethanol was evaporated from the mixture to form apaste, which was dried (80° C., −100 KPa, 8 hours) and grinded to yieldetoposide microparticles (size: about 150 μm).

Preparation of etoposide implants: 3.0 g poly(L-lactic acid) (MW 20,000;melting range 162-168° C.) and 1.0 g polyethylene glycol (4000) weredispersed in ethanol. The mixture is desiccated and grinded to preparemicroparticles of 150 μm in size. The microparticles were weighed, andmixed with etoposide microparticles at a ratio of 1:4 (w/w),respectively. The mixture was compressed to prepare cylindrical granulesof φ 0.9 mm×2 mm in size. Etoposide content in the prepared etoposideimplants was 50.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One etoposide implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 5. In vivo cumulative release of etoposide by the implants wasmeasured. And the results are as shown in Table 5.

TABLE 5 Time 1 day 5 days 10 days 15 days 20 days Cumulative release20.8% 50.5% 69.9% 82.2% 94.7% (%) RSD % 23.1% 16.8% 17.6% 15.2% 12.7%

Example 4

Preparation of cisplatin microparticles: 5.0 g poly(L-lactic acid) (MW20,000; melting range 162-168° C.) was dissolved in chloroform, followedby the addition of 5.0 g cisplatin. The mixture was well-stirred and thesolvent was evaporated. The resulting material was grinded and sieved toprepare cisplatin microparticles (size: about 250 μm).

Preparation of cisplatin implants: 21.0 g poly(L-lactic-glycolic acid)(75/25; MW 16,000; melting range 68-76° C.), 6.0 g polyethylene glycol(4000), 7.0 g cisplatin, and 6.0 g cisplatin microparticles were mixedand extruded at 110° C. to prepare cylindrical granules of φ 0.9 mm×2 mmin size. Cisplatin content in the prepared cisplatin microparticles was25.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One cisplatin implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 6. In vivo cumulative release of cisplatin by the implants wasmeasured. And the results are as shown in Table 6.

TABLE 6 Time 1 day 5 days 10 days 20 days 35 days Cumulative release17.3% 38.9% 55.3% 66.7% 80.2% (%) RSD % 28.4% 24.7% 19.6% 13.5%  8.7%

Example 5

Preparation of cisplatin microparticles: 5.0 g poly(L-lactic acid) (MW20,000; melting range 162-168° C.) was dissolved in chloroform, followedby the addition of 5.0 g cisplatin. The mixture was well-stirred and thesolvent were evaporated. The resulting material was grinded and sievedto prepare cisplatin microparticles (size: about 125 μm).

Preparation of cisplatin implants: 21.0 g poly (L-lactic-glycolic acid)(75/25; MW 16,000; melting range 68-76° C.), 6.0 g polyethylene glycol(4000), 7.0 g cisplatin, and 6.0 g cisplatin microparticles were mixedand extruded at 110° C. to prepare cylindrical granules of φ 0.9 mm×2 mmin size. Cisplatin content in the cisplatin microparticles was 25.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One cisplatin implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 7. In vivo cumulative release of cisplatin by the implants wasmeasured. And the results are as shown in Table 7.

TABLE 7 Time 1 day 5 days 10 days 20 days 30 days Cumulative release22.6% 43.7% 65.3% 78.7% 85.4% (%) RSD % 33.5% 26.1% 19.6% 13.5%  6.6%

Example 6

Preparation of dexamethasone microparticles: 4.0 g dextran (40) wasdissolved in 75% ethanol, followed by the addition of 10.0 gdexamethasone to create a mixture. Ethanol was evaporated to form apaste, which was desiccated (80° C., −100 KPa, 8 hours), and grinded toprepare dexamethasone microparticles (size: about 150 μm).

Preparation of dexamethasone implants: 5.0 g poly (L-lactic acid) (MW20,000; melting range 162-168° C.) and 1.0 g polyethylene glycol (4000)were dispersed in ethanol. The mixture was desiccated, grinded, andsieved to prepare microparticles of a size below 150 μm. Thesemicroparticles were weighed, and mixed with dexamethasone microparticlesat a ratio of 3:7 (w/w), respectively. The mixture was compressed toprepare cylindrical granules of φ 0.9 mm×2 mm in size. Dexamethasonecontent in the prepared dexamethasone implants was 50.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One dexamethasone implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 8. In vivo cumulative release of dexamethasone by the implantswas measured. And the results are as shown in Table 8.

TABLE 8 Time 1 day 5 days 10 days 20 days 30 days Cumulative release17.1% 41.4% 55.5% 73.6% 87.3% (%) RSD % 42.8% 33.3% 17.0% 15.3% 11.5%

Example 7

Fluorouracil implants prepared in Example 2 were implanted into dogperitoneum and abdominal aorta in this experiment to study: (1) localand systemic toxic effects after the implantation of fluorouracilimplants; and (2) the time courses of drug concentration in the areasnear the implantation sites.

Healthy adult mongrel dogs were numbered, dewormed, inspected, andweighed before the operation. Dog were fasted but allowed to have freeaccess to water before the operation. After intraperitoneal anesthesiawith 3% penotobarbital sodium solution (30 mg/kg), peritoneum wasdissected near the center of the upper abdomen. 100 mg fluorouracilimplants were implanted into a site near abdominal aorta, which was thenlabeled by using methylene blue staining. 100 mg fluorouracil implantswere also implanted into sites under left and right peritoneum,respectively, wherein the sites were 5 cm away from the incision.Peritoneum was sutured thereafter.

4 dogs were sacrificed at the third day, fifth day, seventh day, andtenth day after implantation of fluorouracil implants, respectively.Implantation sites were examined for signs of hyperemia, adhesion,infection, and necrosis. Thereafter, the following samples were takenfrom the dogs: lymphoid tissues at various distances from implantationsites near abdominal aorta, lymphoid tissues above the left clavicle,peritoneal tissues within 0-5 cm of the peritoneal implantation sites,peripheral blood samples, and portal vain blood samples. Drugconcentrations in the above samples were determined using HPLC.

No systemic toxic effects were observed during the study period. Theactivities of the dogs were normal, and no signs of anorexia or foodrefusal were observed.

Damage at implantation site: No necrosis was observed under naked eye atthe implantation sites. A few cases of inflammatory cell infiltrationwere observed using pathological inspection.

The time courses of drug concentrations in the areas near theimplantation sites are listed in Tables 9-11.

TABLE 9 Drug concentrations in peritoneal tissues near the peritonealimplantation site (μg/g) Distance from implantation site (cm) Time n 0 12 3 4 5  3 d 4 52.53 ± 35.20 15.12 ± 11.54 5.32 ± 4.31 3.48 ± 2.74 2.33± 2.21 0.92 ± 0.73  5 d 4 46.93 ± 37.23 10.40 ± 8.81  3.50 ± 2.73 2.80 ±2.19 1.82 ± 1.57 0.71 ± 0.62  7 d 4 42.64 ± 28.83 9.64 ± 7.63 2.64 ±1.94 2.29 ± 1.63 1.48 ± 1.30 0.64 ± 0.44 10 d 4 36.54 ± 32.31 5.12 ±3.40 1.83 ± 1.30 1.71 ± 0.55 0.57 ± 0.22 0.24 ± 0.13

TABLE 10 Drug concentrations in lymphoid tissues near the abodominalaorta implantation site (μg/g) Distance from implantation site (cm) Timen 0 3 5 10 3 d 4 48.5 ± 42.2 6.3 ± 4.3 4.3 ± 3.2 1.3 ± 0.6 5 d 4 46.9 ±36.3 5.5 ± 3.7 2.8 ± 0.8 1.0 ± 0.8 7 d 4 41.6 ± 32.8 3.6 ± 1.9 1.5 ± 1.10.8 ± 0.7 10 d  4 38.5 ± 24.3 2.0 ± 1.7 0.8 ± 0.2 0.4 ± 0.3

TABLE 11 Drug concentration after implantation of the controlled releasefluorouracil implants (μg/g) Time (days) Sites n 3 5 7 10 Peripheral 40.04 ± 0.01 0.02 ± 0.01 Not Not blood detected detected Portal vein 40.6 ± 0.2  0.3 ± 0.18 0.2 ± 0.09 0.08 ± 0.06 blood

Example 8

Preparation of lidocaine hydrochloride microparticles: 1.6 gEthylcellulose was dissolved completely in chloroform, and mixed with2.4 g lidocaine hydrochloride. The mixture was evaporated until dry, andthe resulting solid was grinded to yield lidocaine hydrochloridemicroparticles of about 125 μm in size.

Preparation of lidocaine hydrochloride implants: 2.4 g octadecanol, 3.0g lidocaine hydrochloride microparticles and 0.6 g lidocainehydrochloride were mixed and injection molded at 65° C. Cylindricalgranules about φ 0.9 mm×4 mm in size were prepared. The content oflidocaine hydrochloride in the lidocaine hydrochloride implant was40.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. Two lidocaine hydrochloride implants were implanted into themedial hind leg muscle of each mouse. Samples were collected at timepoints as indicated in Table 12. In vivo cumulative release of lidocainehydrochloride by the implants was measured. The results are as shown inTable 12.

TABLE 12 Time 1 day 2 days 3 days 5 days 7 days Cumulative release 28.8%47.5% 60.9% 83.7% 94.4% (%) RSD % 30.3%  9.6% 15.6% 14.1%  8.7%

Example 9

Preparation of methotrexate microparticles: 2.0 g Carnauba wax (meltingpoint: 81-88° C.) and 3.0 g Methotrexate were mixed and melted at 95° C.The melted mixture was cooled and the resulting solid was grinded toyield the methotrexate microparticles of about 100 μm in size.

Preparation of methotrexate implant: 3.0 g polycaprolactone (meltingpoint: about 62° C.) and 3.0 g methotrexate microparticles were mixedand compressed. Cylindrical granules about p 0.9 mm×2.0 mm in size wereprepared. The content of methotrexate in the prepared methotrexateimplant was 30.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One methotrexate implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 13. In vivo cumulative release of methotrexate by the implantwas measured. The results are as shown in Table 13.

TABLE 13 Time 1 day 5 days 10 days 15 days 20 days Cumulative release18.5% 49.9% 69.2% 80.0% 90.6% (%) RSD % 22.3% 30.6% 15.2% 15.5%  9.6%

Example 10

Preparation of doxorubicin hydrochloride microparticles: 1.0 g Carnaubawax (melting point: about 81-88° C.) and 1.5 g doxorubicin hydrochloridewere mixed and melted at 95° C. The melted mixture was cooled and theresulting solid was grinded to yield the doxorubicin hydrochloridemicroparticles of about 100 μm in size.

Preparation of doxorubicin hydrochloride implants: 2.0 gpoly(lactide-co-glycolide) (L-lactide/glycolide=90/10, molecular weight2.0×10⁴, melting range: 70-79° C.) and 2.0 g doxorubicin hydrochloridemicroparticles were mixed and compressed. Cylindrical granules aboutφ0.9 mm×2.0 mm in size were prepared. The content of doxorubicinhydrochloride in the prepared doxorubicin hydrochloride implant was30.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One doxorubicin hydrochloride implant was implanted into themedial hind leg muscle of each mouse. Samples were collected at timepoints as indicated in Table 14. In vivo cumulative release ofdoxorubicin hydrochloride by the implant was measured. The results areas shown in Table 14.

TABLE 14 Time 1 day 5 days 10 days 15 days 20 days Cumulative release25.2% 53.6% 70.5% 78.4% 87.0% (%) RSD % 27.1% 11.8% 20.2% 12.7%  4.3%

Example 11

Preparation of gentamicin sulphate: 1.5 g Carnauba wax (melting point:81-88° C.), and 3.5 g gentamicin sulphate were mixed and melted at 95°C. The melted mixture was cooled and the resulting solid was grinded toyield the gentamicin sulphate microparticles of about 100 μm in size.

Preparation of gentamicin sulphate implant: 2.0 gpoly(lactide-co-glycolide) (L-lactide/glycolide=75/25, molecular weight2.0×10⁴, melting range: 68-76° C.), and 2.0 g gentamicin sulphatemicroparticles were mixed and compressed. Cylindrical granules aboutφ0.9 mm×2.0 mm in size were prepared. The content of gentamicin sulphatein the prepared gentamicin sulphate implant was 35.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One gentamicin sulphate implant was implanted into the medialhind leg muscle of each mouse. Samples were collected at time points asindicated in Table 15. In vivo cumulative release of gentamicin sulphateby the implant was measured. The results are as shown in Table 15.

TABLE 15 Time 1 day 5 days 10 days 15 days 20 days Cumulative release27.1% 56.8% 70.0% 85.6% 94.3% (%) RSD % 27.6% 27.9% 12.2% 6.4% 2.1%

Example 12

Preparation of mycophenolate mofetil microparticles: 2.0 gpoly(L-lactide) (molecular weight: 2.0×10⁴, melting range: 162-168° C.)was dissolved in chloroform, and the solution was mixed with 3.0 gmycophenolate mofetil. Chloroform is evaporated until dry, and theresulting solid was grinded to yield mycophenolate mofetilmicroparticles of about 100 μm in size.

Preparation of mycophenolate mofetil implant: 2.0 g poly(CPP-SA)(CPP/SA=22/78, melting point: 66° C.), and 1.5 g mycophenolate mofetilmicroparticles, 0.5 g mycophenolate mofetil were mixed and extruded at100° C. Cylindrical granules about 90.9 mm×2.0 mm in size were prepared.The content of mycophenolate mofetil in the prepared mycophenolatemofetil implant was 35.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One mycophenolate mofetil implant was implanted into the medialhind leg muscle of each mouse. Samples were collected at time points asindicated in Table 16. In vivo cumulative release of mycophenolatemofetil by the implant was measured. The results are as shown in Table16.

TABLE 16 Time 1 day 5 days 10 days 15 days 20 days Cumulative release21.9% 49.8% 63.3% 77.7% 85.3% (%) RSD % 15.3% 18.1% 8.7% 10.0% 1.9%

Example 13

Preparation of fluorouracil microparticles: 80.0 g fluorouracil, 20.0 gmethyl methacrylate, 0.01 g perbenzoic acid were mixed and reacted at50-100° C. under normal pressure. The resulting mixture was cooled andgrinded to yield fluorouracil microparticles of about 100 μm in size.

Preparation of fluorouracil implant: 10.0 g poly(L-lactide), 15.0 gfluorouracil microparticles were injection molded at 165° C. Cylindricalgranules about φ0.9 mm×4.0 mm in size were prepared. The content offluorouracil in the prepared fluorouracil implant was 47.8%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One fluorouracil implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 17. In vivo cumulative release of fluorouracil by the implantwas measured. The results are as shown in Table 17.

TABLE 17 Time 1 day 10 days 20 days 30 days 40 days Cumulative release12.7% 40.0% 61.9% 79.2% 88.8% (%) RSD % 31.3% 31.8% 10.7% 5.5% 2.3%

Example 14

Preparation of lidocaine hydrochloride microparticles: 2.0 gpoly(lactide-co-glycolide) (L-lactide/glycolide=75/25, molecular weight2.0×10⁴, melting range: 68-76° C.), 3.5 g lidocaine hydrochloride weremixed and melted at 100° C. The melted mixture was cooled and theresulting solid was grinded to yield the lidocaine hydrochloridemicroparticles of about 100 μm in size.

Preparation of lidocaine hydrochloride implant: 2.0 g lidocainehydrochloride microparticles were mixed in 15 ml 15% gelatin solution,and injected into a mold. After evaporation, the resulting product wasimmersed in 5 glutaraldehyde solution for 1 hour, and then taken out forevaporation to prepare film sheets. The content of lidocainehydrochloride in the prepared lidocaine hydrochloride implant was 32.1%.

The in vitro release profile was measured by static dissolution methodusing phosphate buffer (pH=7.4) as release medium. Samples werecollected at time points as indicated in Table 18. In vivo cumulativerelease of lidocaine hydrochloride by the implant was measured. Theresults are as shown in Table 18.

TABLE 18 Time 1 day 2 days 3 days 4 days Cumulative release 42.2% 68.9%82.5% 95.6% (%) RSD % 33.3% 15.9% 12.2% 7.5%

Example 15

Cisplatin implant prepared according to Example 5 was used in thisstudy. Ascites fluid was taken from d7 H22 passage mice under sterileconditions, and the ascites fluid was diluted with normal saline toprepare tumor cell suspension at a concentration of 1.0×10⁷ cells/ml.Each mouse received a subcutaneous injection of 0.2 ml tumor cellsuspension at the right armpit (number of inoculated cells: 2×10⁶). Themice were randomized into 6 groups the next day after inoculation,cisplatin implant or excipient control was implanted near the tumor atthe seventh day after inoculation. The positive control group receivedan intraperitoneal injection of cisplatin the next day afterinoculation, and four injections in total at an interval of twice aweek. The negative control group received an intraperitoneal injectionof normal saline the next day after inoculation, and four injections intotal at an interval of twice a week. The mice were sacrificed at the15th day after inoculation, and the tumor mass were peeled and weighted.Tumor growth inhibition rate was calculated using the followingequation:

${{tumor}\mspace{14mu} {growth}{\mspace{11mu} \;}{inhibition}\mspace{14mu} {rate}} = {\frac{\begin{matrix}{{{tumor}\mspace{14mu} {weight}{\mspace{11mu} \;}{of}\mspace{14mu} {control}\mspace{14mu} {group}} -} \\{{tumor}\mspace{14mu} {weight}\mspace{14mu} {of}\mspace{14mu} {treated}{\mspace{11mu} \;}{group}}\end{matrix}}{{tumor}\mspace{14mu} {weight}{\mspace{11mu} \;}{of}\mspace{14mu} {control}\mspace{14mu} {group}} \times 100\%}$

TABLE 19 Tumor growth Number of inhibition Route of animals Tumor weightrate Group Dose Administration onset end X ± SD (g) (%) P value Normal —i.p. 20 20 3.71 ± 1.13 — Saline Excipient — Near the tumor 15 13 3.67 ±1.34 — cisplatin 12 mg/kg i.p. 15 15 2.98 ± 1.14 19.68 Cisplatin implantd7 20 mg/kg Near the tumor 15 15 2.06 ± 0.73 43.87 <0.05 10 mg/kg Nearthe tumor 15 15 2.31 ± 0.68 37.05 <0.05  5 mg/kg Near the tumor 15 122.92 ± 0.98 20.43

Example 16

14 patients with non-small cell lung cancer were treated with cispatinimplant prepared according to Example 5. The cisplatin implant wasimplanted into the tumor through CT-guided percutaneous puncture. Aftertreatment, 3 patients showed significantly decreased disease focus, 8patients showed stabilized disease focus, while 3 patients showeddisease progression. The observed adverse effects included: nausea,vomiting, decreased appetite, lack of strength, local pain, fewhemoptysis, and low-grade fever. The adverse effects generallydisappeared after symptomatic treatment.

Example 17

Fluorouracil implant prepared according to Example 2 were used in thisstudy. SGC-7901 tumor tissues at vigorous growth stage were obtained andcut into pieces of about 1.5 mm³. The tumor tissue pieces wereinoculated subcutaneously to the right armpit of nude mice, understerile conditions. The mice were randomized into 6 groups at the sixthday after inoculation. Three groups were treated with different doses offluorouracil implant prepared according to Example 2. Another group wastreated with excipient at the sixth day after noculation. Thefluorouracil implant or excipient was implanted subcutaneously near thetumor. The positive group received four intraperitoneal injections offluorouracil in total at an interval of twice a week. The negativecontrol group received four intraperitoneal injections of normal salinein total at an interval of twice a week. The mice were sacrificed at the21st day after inoculation, and the tumor mass were peeled and weighed.The tumor growth inhibition rate was calculated using the followingequation:

${{tumor}\mspace{14mu} {growth}{\mspace{11mu} \;}{inhibition}\mspace{14mu} {rate}} = {\frac{\begin{matrix}{{{tumor}\mspace{14mu} {weight}{\mspace{11mu} \;}{of}\mspace{14mu} {control}\mspace{14mu} {group}} -} \\{{tumor}\mspace{14mu} {weight}\mspace{14mu} {of}\mspace{14mu} {treated}{\mspace{11mu} \;}{group}}\end{matrix}}{{tumor}\mspace{14mu} {weight}{\mspace{11mu} \;}{of}\mspace{14mu} {control}\mspace{14mu} {group}} \times 100\%}$

TABLE 20 Tumor Tumor growth Number of weight inhibition Dose Route ofanimals X ± SD (g) rate P Group per rat Administration onset end onsetend (%) value Grou

NS — ip 16 16 23.1 25.4 2.93 ± 0.90 — excipient — Near the 8 8 23.6 26.22.99 ± 0.81 — tumor 5-FU  1.6 mg ip 6 6 21.0 22.8 0.71 ± 0.42 75.76 <0.0

5-FU implant d6   4 mg Near the 6 5 20.7 21.7 0.02 ± 1.05 99.33 <0.0

tumor   1 mg Near the 6 6 20.2 21.2 0.40 ± 0.37 86.62 <0.0

tumor 0.25 mg Near the 6 6 19.9 22.0 1.27 ± 1.29 57.52 <0.0

tumor

indicates data missing or illegible when filed

Example 18

24 patients with colorectal cancer were treated with etoposide implants.Etoposide implants were prepared according to Example 3. The 24 patientswho were aged about 45-65 planned to do surgical operation. Thepathological diagnosis of the patients was clear and indicate they werein Dukes B-C stage. The patients could tolerate to operation andchemotherapy. Consent was obtained from each patient's relative forthose patient grouped into the etoposide implant treatment group.

The patients were paired according to sex, diseased area, pathologicalstage, and pathological type. The patients were grouped into two groups.Group I (n=14) were treated with etoposide implant. Each patient inGroup I received a total amount of 200 mg etoposide implant under therectal mucosa 7 days before the surgical operation. The etoposideimplant was implanted into 3 channels located 1-3 cm above the rectaldentate line, and 60-70 mg etoposide implant were implanted to eachchannel. Group II (n=10) were treated with conventional treatment.Biopsy tissue blocks were collected from all patients prior tooperation, and were used as control tissue sample for drug implantedtissue. Operation was performed 168 hours after the drug implant. Afterthe operation, tissue blocks of about 1.0 cm×1.0 cm×0.5 cm in size werecut from tumor site and implanted site, respectively (biopsy sampleswere obtained from anal after operation if tissue blocks cannot be cutbecause of tumor fixation). The obtained tissue blocks were fixed by 10%formaldehyde solution, followed by dehydration, clarification, embeddedwith wax, and buried. Regular HE staining is applied to the preparedtissue slices followed by pathological analysis.

Results showed that, 14 patients in the implant group showed neithernecrosis in mucosa at implant site, nor ulceration, and few bruise wasobserved under the mucosa. The colorectal cancer tissue slice wasstained with HE and the result showed, the pathological morphology wasranked 0 degree before drug implant, after chemotherapy, 14 patientsshowed I-II grade change (0: no change; 1 grade: cancer cells swell, andthe hollow vesicle denatured, the nuclears of some cancer cellscondensed or dissolved, glandular tubes and cancer nests were basicallynot destroyed; II grade: most of the cancer cells showed significantdenaturation, a majority of cells showed condensed nuclear or dissolvednuclear, cancer nests were detached from the glandular tubes; III grade:most of the cancer cells were dead, and cancer nests were dissolved andalmost collapsed and disappeared.) More than ⅕ cancer cells on the sliceshowed spoty or pathy degeneration, and the nuclears are dissolved andcondensed. The 10 patients in control group showed no obvious change inpathology before and after operation.

Before drug implant, there was no significant difference between theapoptosis index (AI, AI=(number of apoptosis cells/number of totalcancer cells)×100%) and the proliferation index (PI, PI=number of PCNApositive cells/number of total cancer cells)×100%). The AI and PI didnot show any significant change in non-implant group after treatment.The implant group showed increased AI and decreased PI after operation.The AI and PI of cancer tissue obtained in biopsy before drug implantwere compared with the AI and PI of tissue slice after drug implant, andthe results showed that the two had statistically significant difference(P<0.01).

TABLE 21 AI and PI of cancer cells from patients in Group I (n = 14)before and after drug implant (x ± s) AI PI Before implant 1.320 ± 0.66846.33 ± 11.48 After implant 3.623 ± 1.235 39.62 ± 16.44

When etoposide implants were implanted beneath the colon mucosa, theimplant site did not show hemorrhage, nor obvious infection. 168 hoursafter the drug implant, the pathological examination on the implant siteshowed a few signs filtration of inflammatory cells, no necrosis wasobserved for colon mucosa or muscle tissues, and no ulceration,bleeding, necrosis or infection was observed at the implant site. Nosystemic adverse effects were observed in blood routine test, liver andrenal function test, electrocardiogram tests.

Example 19

Fluorouracil implant composition prepared according to Example 2 wastested for its efficacy on pancreatic cancer. Pancreatic cancer cellline PC3 was cultured and inoculated subcutaneously to 70 nude mice atthe right armpit at the dose of 2×10⁶ cells per inoculation. Tumor grewto the size of about 4 mm×4 mm×4 mm 4 weeks after the implant. 60 nudemice having tumors of similar sizes were selected and randomized into 5groups with 12 mice in each group:

Group A was administered intravenously through the angular vein withnormal saline at the dose of 0.1 ml per mice; Group B was administeredintravenously through the angular vein with 0.1 ml fluorouracil solutionin normal saline at the dose of 10 mg/kg; Group C was implanted withblank matrix; Group D was implanted with fluorouracil implantcomposition into the pancreatic tumor mass at the dose of 4 mg/kg; andGroup E was implanted with fluorouracil implant composition into thepancreatic tumor mass at the dose of 1 mg/kg. The size of the tumor masswas measured before and after treatment. The results are shown in Table22.

TABLE 22 Change in tumor size before and after treatment (mm³) Aftertreatment Group Before treatment 3rd day 6th day 10th day 14th day A60.9 ± 8.3 82.2 ± 19.5 119.3 ± 18.4 147.2 ± 22.8 169.4 ± 12.2 B 61.5 ±8.7 72.3 ± 14.6 96.62 ± 20.5 107.3 ± 20.9 121.6 ± 14.3 C 59.4 ± 9.2 83.7± 11.0 125.4 ± 14.3 154.7 ± 13.1 178.0 ± 20.2 D 60.3 ± 9.0 64.0 ± 13.572.8 ± 8.9  76.1 ± 19.2  82.5 ± 10.3 E 58.7 ± 8.6 63.1 ± 7.6  44.9 ± 9.081.4 ± 8.6  85.5 ± 12.3

Example 20

Mycophenolate mofetil implant composition prepared according to Example12 was tested for its efficacy on renal inflammation.

30 female SD rats with body weigh ranging from 150 g to 170 g wererandomized into 3 groups with 10 rats in each group. Each of controlgroup, diseased group and treatment group has 10 rats. Rats in thediseased group and rats in the treatment group were both administeredwith one injection of doxorubicin at the dose of 7.5 mg/kg through tailvein. Rats in the control group were administered with one injection ofequal volume of normal saline. The rats were fed with standard forageand allowed to free access to food and water. At the 2nd day afterinjection of doxorubicin, rats in the treatment group were implantedwith 20 mg/kg mycophenolate mofetil implant at capsula renis at bothleft side and right side, and rats in the diseased group and rats in thecontrol group were gavaged with equal volume of distilled water. Raturine were collected for 24 hours one day before the injection ofdoxorubicin/normal saline, at the 14th day and the 28th day after theinjection, and the protein amount was measured in the urine samplescollected. If the protein amount in the urine sample collected at the14th day was above 150 mg/24 hours, the rat was considered a successfulanimal model and was counted into the study. All rats were sacrificed atthe 28th day after the injection, and levels of total protein (TP),albumin protein (ALB), triglyceride (TG), cholesterol (Chol), ureanitrogen (BUN), and creatinine (Cr) were measured.

TABLE 23 Amount of urine protein in the three groups of rats (mg/24 h, n= 10) Control group Diseased group Treatment group  0 day  9.98 ± 1.95 9.98 ± 1.67  10.59 ± 2.11 14th day 11.57 ± 2.14 219.41 ± 15.24* 243.89± 10.78 28th day 12.87 ± 2.86 304.27 ± 21.04* 168.02 ± 12.85# *P < 0.01as compared with the control group; #P < 0.01 as compared with thediseased group

TABLE 24 Biochemical index of three groups of rats (n = 10) TP ALB TGChol BUN Cr 28th day (g/L) (g/L) (mmol /L) (mmol/L) (mmol/L) (μmol/L)Control group 51.50 ± 7.82 30.37 ± 3.18 0.68 ± 0.21 1.58 ± 0.55 6.57 ±1.68 57.01 ± 4.47 Diseased group 36.34 ± 5.75* 16.55 ± 1.59* 6.32 ±0.76* 8.72 ± 1.01* 7.92 ± 1.02 63.28 ± 7.46 Treatment group  50.8 ±8.62^(#)  33.8 ± 4.67^(#) 0.87 ± 0.31^(#) 1.68 ± 0.755^(#) 5.82 ± 2.38 69.9 ± 12.47 *P < 0.01 as compared with the control group; ^(#)P < 0.01as compared with the diseased group

Example 21

Gentamicin sulphate implant prepared according to Example 11 was testedfor local distribution and diffusion after intramuscular implantation.

35 mongrel dogs, including 14 female dogs and 21 male dogs, were dividedinto 7 groups, and each group included 2 female dogs and 3 male dogs.Each dog was implanted with gentamicin sulphate implant at the bicepsfemoris muscle at the outer side of the right hind leg at the dose of 10mg/kg. One group of dogs were sacrificed at a given time point, and thehind leg having implanted drug was obtained and frozen without skin.Muscle tissue samples were taken from the areas around the implantationsite. X axis and Y axis were set on the muscle tissue with the originbeing the implantation site. Muscle tissues were sampled along the Xaxis and Y axis at an interval of 10 mm. Concentrations of gentamicinsulphate in the muscle tissue samples were measured to study thedistribution and diffusion of gentamicin sulphate after implantation inthe muscle. The results are shown in Table 25.

TABLE 25 24 h 72 h 120 h 240 h 360 h 480 h X − 3 cm  91.16 ± 17.30 63.38 ± 14.90  47.66 ± 11.95 35.66 ± 9.61 27.56 ± 8.10 16.88 ± 6.63 Y −3 cm  90.82 ± 15.29  63.22 ± 15.47  46.14 ± 10.40 34.84 ± 9.69 27.36 ±8.68 17.22 ± 7.69 X − 2 cm 169.10 ± 54.87 109.72 ± 22.62  74.42 ± 14.5242.40 ± 15.28 31.26 ± 11.55 26.12 ± 9.69 Y − 2 cm 167.82 ± 59.04 106.18± 22.53  74.88 ± 13.22 41.30 ± 14.43 30.58 ± 10.81 25.90 ± 8.42 X − 1 cm304.06 ± 69.04 223.66 ± 54.84 134.62 ± 24.89 70.85 ± 11.34 46.73 ± 12.0835.96 ± 8.66 Y − 1 cm 294.60 ± 71.70 204.46 ± 45.24 127.62 ± 29.63 71.46± 7.32 44.80 ± 13.16 36.54 ± 9.21 0 586.80 ± 56.55 458.74 ± 54.09 307.90± 77.54 113.6 ± 37.01 75.20 ± 24.18 58.30 ± 24.38 Y + 1 cm 312.58 ±86.84 211.48 ± 21.33 136.64 ± 14.62 64.72 ± 11.37 44.66 ± 11.19 36.62 ±8.19 X + 1 cm 305.12 ± 86.91 217.56 ± 52.20 135.12 ± 25.73 69.30 ± 8.2144.48 ± 13.02 34.48 ± 8.51 Y + 2 cm 170.22 ± 51.72 111.34 ± 50.74  74.02± 14.27 42.84 ± 13.14 29.62 ± 11.14 24.98 ± 8.64 X + 2 cm 167.66 ± 52.48110.24 ± 25.46  74.68 ± 16.88 41.06 ± 12.76 31.34 ± 11.31 27.40 ± 9.85Y + 3 cm  89.68 ± 15.16  61.56 ± 15.08  47.80 ± 11.59 36.22 ± 9.73 27.58± 8.15 17.14 ± 6.94 X + 3 cm  89.94 ± 18.81  62.34 ± 15.60  47.60 ±10.69 36.08 ± 9.16 29.10 ± 7.58 15.96 ± 7.39

Example 22

Lidocaine hydrochloride implant prepared according to Example 8 wasadministered to 10 breast cancer patients during surgical operation,where 5 patients were administered at the dose of 50 mg/patient, and 5patients were administered at the dose of 100 mg/patient. Afterimplantation, none of the 10 patients demonstrated sensible pain at theoperation region.

Example 23

Preparation of nifedipine microparticles: 2 g ethylcellulose and 3 gnifedipine were mixed and completely dissolved in chloroform. Thesolvent chloroform was evaporated until dry. The resulting solid wasgrinded to yield microcparticles of about 90 μm in size.

Preparation of Nifedipine implant: 2 g poly(lactide-co-glycolide)(L-lactide/glycolide=90/10, molecular weight 1.6×10⁴, meltingtemperature range: 68˜76° C.), 0.3 g polyethylene glycol (4000), and 3.7g nifedipine microparticles were mixed and compressed to preparecylindrical granules of φ 0.9 mm×2 mm in size. Nifedipine content in theprepared nifedipine implants was 37.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One nifedipine implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 26. In vivo cumulative release of nifedipine by the implantswas measured. And the results are as shown in Table 26.

TABLE 26 Time (day) 1 day 5 days 10 days 15 days 20 days Cumulativerelease (%) 16.7% 42.3% 63.1% 74.9% 83.3% RSD % 20.5% 17.2% 7.3% 12.5%4.4%

Example 24

Dry powders of PLGA (intrinsic viscosity: 33.40) were compresseddirectly into tablets and implanted subcutaneously at the back of therat. The degradation of the implant was shown in Table 27.

TABLE 27 Retention time in rat Weight loss (%) Intrinsic viscosity 0 day33.40 1 week 4.31 29.69 4 weeks 10.17 23.18 6 weeks 12.47 18.70 9 weeks25.64 19.26 12 weeks 45.62 18.04 15 weeks 56.51 17.14

Example 25

Dry powders of PLLA (intrinsic viscosity: 47.21) were compresseddirectly into tablets and implanted subcutaneously at the back of therat. The degradation of the implant was shown in Table 28.

TABLE 28 Retention time in rat Weight loss (%) Intrinsic viscosity 0 day47.21 1 week 3.46 48.38 2 weeks 3.13 47.03 4 weeks 8.46 43.77 12 weeks19.33 42.83 26 weeks 27.30 36.51 31 weeks 29.26 27.73 41 weeks 29.2625.19 46 weeks 29.64 22.80 52 weeks 43.72 19.91

Example 26

Preparation of fluorouracil microparticles: 5% silicone rubber solutionwas prepared using cyclohexane and used as the coating solution.Fluorouracil powders were coated and solidified for 10 times by thecoating solution. The fluorouracil content in the microparticles were94.8%.

Preparation of fluorouracil micro-implant: 5.0 g poly(L-lactide) and 9.0g fluorouracil microparticles were mixed. Cylindrical granules about90.9 mm×4.0 mm in size were prepared by melt injection moulding method.The content of fluorouracil in the prepared fluorouracil implant was60.9%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One fluorouracil implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 29. In vivo cumulative release of fluorouracil by the implantswas measured. And the results are as shown in Table 29.

TABLE 29 Time (day) 1 day 10 days 30 days 50 days 70 days Cumulativerelease (%) 6.5% 31.8% 53.9% 70.7% 85.5% RSD % 37.2% 25.1% 19.3% 19.1%10.4%

Example 27

The release profile of fluorouracil micro-implant provided in Example 26was compared with the release profile of the fluorouracil micro-implantprepared without the second material.

The fluorouracil micro-implant without the second material was preparedas follows: 5.0 g poly(L-lactide) and 7.8 g fluorouracil were mixed.Cylindrical granules about φ0.9 mm×4.0 mm in size were prepared by meltinjection moulding method. The fluorouracil in the prepared fluorouracilimplant was 60.9%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One fluorouracil implant was implanted into the medial hind legmuscle of each mouse. Samples were collected at time points as indicatedin Table 30. In vivo cumulative release of fluorouracil by the implantswas measured. And the results are as shown in Table 30.

TABLE 30 Time (day) 1 day 3 days 5 days 7 days 10 days Cumulativerelease (%) 28.5% 55.6% 67.1% 77.0% 87.3% RSD % 42.3% 30.3% 10.0% 5.1%1.1%

The fluorouracil content in the fluorouracil micro-implant of Example 26and in the fluorouracil micro-implant of Example 27 were the same, bothwere of 60.9% weight percentage of the implant. Therefore the percentageof released fluorouracil were compared. Table 29 shows that the implantof Example 26 released about 31% of fluorouracil after 10 days, butimplant of Example 27 released about 87% of fluorouracil after 10 daysas shown in Table 30. The implant of Example 26 continued to releasefluorouracil even 70 days after the implantation. The results showedthat fluorouracil implant of Example 26 demonstrated a significantlylonger release period than that achieved by the implant of Example 27.

Example 28

Preparation of gentamicin sulphate microparticles: 3.0 g Carnauba wax(melting temperature range: 81-88° C.) and 7.0 g gentamicin sulphatewere mixed and melted at 95° C. The melted mixture was cooled and theresulting solid was grinded to yield the gentamicin sulphatemicroparticles of about 100 μm in size.

Preparation of gentamicin sulphate implant: 7.2 g (L-lactide-glycolide)(L-lactide/glycolide=75/25, molecular weight 2.0×10⁴, meltingtemperature range 68-76° C.), 8.0 g gentamicin sulphate microparticlesand 8.0 g stearyl alcohol were mixed. The mixed powders were compresseddirectly into tablets to prepare gentamicin sulphate implant. Thegentamicin sulphate content in the gentamicin sulphate implant was35.0%.

Thirty Kunming mice were randomized into 5 groups with 6 mice in eachgroup. One gentamicin sulphate implant was implanted into the medialhind leg muscle of each mouse. Samples were collected at time points asindicated in Table 31. In vivo cumulative release of gentamicin sulphateby the implants was measured. And the results are as shown in Table 31.

TABLE 31 Time (day) 1 day 5 days 10 days 15 days 20 days Cumulativerelease (%) 21.1% 50.5% 63.9% 76.7% 85.5% RSD % 22.7% 8.2% 11.3% 10.1%2.4%

Example 29

6 mongrel dogs, including 3 females and 3 males, were dewormed andfasted for 12 hours. Each dog was implanted with gentamicin sulphateimplant at the biceps femoris muscle at the outer side of the right hindleg at the dose of 20 mg/kg. Blood samples were drawn from theperipheral veins at given time points and placed in tubes coated withanticoagulant. The concentration of gentamicin sulphate in the bloodsamples were measured and the results were shown in Table 32.

TABLE 32 Concentration Time (Hour) (μg/ml) RSD % 2 2.80 1.96 4 1.96 2.946 1.18 4.91 8 1.07 5.19 12 0.86 6.24 24 0.72 7.66 48 0.60 8.63 72 0.4810.87 96 0.42 11.95 120 0.33 17.35 168 0.26 19.46 216 0.17 35.68 2400.13 38.00 312 0.07 71.47

6 mongrel dogs, including 3 females and 3 males, were dewormed andfasted for 12 hours. Each dog was injected with gentamicin sulphateinjection at the biceps femoris muscle at the outer side of the righthind leg at the dose of 20 mg/kg. Blood samples were drawn from theperipheral veins at given time points and placed in tubes coated withanticoagulant. The concentration of gentamicin sulphate in the bloodsamples were measured and the results were shown in Table 33.

TABLE 33 Concentration Time (μg/ml) RSD % 5 min 11.35 11.70 10 min 15.618.62 15 min 19.60 7.09 30 min 25.17 4.95 45 min 31.73 4.14 1 h 40.733.11 1.5 h 35.39 3.84 2 h 31.77 4.15 3 h 26.69 4.85 4 h 13.58 9.08 8 h3.76 32.62 16 h 0.52 91.49 24 h <0.02 N/A

While the invention has been disclosed in its preferred forms, it willbe apparent to those skilled in the art that many modifications,additions, and deletions can be made therein without departing from thespirit and scope of the invention and its equivalents as set forth inthe following claims.

1. A controlled release composition comprising a plurality of microparticles operably linked to a matrix, wherein: the plurality of microparticles comprises a first material and a first active agent; the matrix comprises a second material; the first material comprises an initial melting temperature T_(H); the second material comprises a complete melting temperature T_(L); ΔT=T_(H)−T_(L); and ΔT>0.
 2. The controlled release composition of claim 1, wherein the first material or the second material is a polymer or a non-polymeric organic compound.
 3. The controlled release composition of claim 2, wherein the first material and the second material are either a polymer or a non-polymeric organic compound.
 4. The controlled release composition of claim 2, wherein the first material is a polymer and the second material is a non-polymeric organic compound.
 5. The controlled release composition of claim 2, wherein the first material is a non-polymeric organic compound and the second material is a polymer.
 6. The controlled release composition of claim 2, wherein the first material is a combination of a polymer and a non-polymeric organic compound.
 7. The controlled release composition of claim 2, wherein the second material is a combination of a polymer and a non-polymeric organic compound.
 8. The controlled release composition of claim 1, wherein the first material or the second material comprises a polymer formed by at least one monomer independently selected from the group consisting of: L-lactic acid, saccharide, ethylene glycol oxalate, p-dioxanone, ε-caprolactone, ethylcyanoacrylate, butylcyanoacrylate, β-hydroxybutyrate, 3-hydroxybutyrate, 4-hydroxyvalerate, 1,3-bis(carboxyphenoxy)propane, sebacic acid, D-glucose, acetate of glucose, glucose substituted with hydroxyl groups, glycolic acid, ε-caprolacton, 1,4-dioxan-2-one, sebacic anhydride, dodecanoic anhydride, ethylene glycol, oxyethylene, 1,3-bis(carboxyphenoxy)propane, 3-hydroxyvalerate, caprolactone, methyl methacrylate, gelatin, isoleucine, leucine, alanine, asparagine, lysine, methionine, aspartic acid, cysteine, tryptophan, valine, glycine, proline, serine, tyrosine, arginine, histidine, phenylalanine, glutamic acid, threonine, glutamine, adenine, guanine, thymine, cytosine, and dimethyl siloxane.
 9. The controlled release composition of claim 1, wherein the first material or the second material is independently selected from the group consisting of poly(L-lactic acid), dextran, poly(ethylene glycol oxalate), poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly (β-hydroxybutyrate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, zein, poly(L-lactic-co-glycolic acid), poly(ε-caprolacton), poly(1,4-dioxan-2-one), poly(sebacic anhydride), poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol; ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), Carnauba wax, ethylcellulose, octadecanol, polycaprolactone, poly(methyl methacrylate), poly(gelatin), and silicone rubber.
 10. The controlled release composition of claim 1, wherein the first material is selected from the group consisting of: (i) a combination of poly(L-lactic acid) and at least one compound selected from the group consisting of: dextran, poly(ethylene glycol oxalate), poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly (β-hydroxybutyrate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein; (ii) a combination of poly(ethylene glycol oxalate) and at least one compound selected from the group consisting of: dextran, poly(p-dioxanone-co-c-caprolactone), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly (β-hydroxybutyrate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein; (iii) a combination of poly(β-hydroxybutyrate) and at least one compound selected from the group consisting of: dextran, poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein; (iv) a combination of poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) and at least one compound selected from the group consisting of: dextran, poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein; (v) a combination of poly(butylcyanoacrylate) and at least one compound selected from the group consisting of: dextran, poly(p-dioxanone-co-ε-caprolactone), poly(ethylcyanoacrylate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein; and (vi) a combination of (i), (ii), (iii), (iv), or (v).
 11. The controlled release composition of claim 1, wherein the second material is selected from the group consisting of: (i) a combination of poly(L-lactic-co-glycolic acid) and at least one compound selected from the group consisting of: poly(ε-caprolacton), poly(1,4-dioxan-2-one), poly(sebacic anhydride), poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol; ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate); (ii) a combination of poly(ε-caprolacton) and at least one compound selected from the group consisting of: poly(1,4-dioxan-2-one), poly(sebacic anhydride), poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol; ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate); (iii) a combination of poly(1,4-dioxan-2-one) and at least one compound selected from the group consisting of: poly(sebacic anhydride), poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol; ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate); and (iv) a combination of poly(sebacic anhydride) and at least one compound selected from the group consisting of: poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol; ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate); and (v) a combination of (i), (ii), (iii), or (iv).
 12. The controlled release composition of claim 1, wherein the first material and the second material is a pair of materials selected from the group consisting of: poly(L-lactic acid) and poly(L-lactic-co-glycolic acid); poly(L-lactic acid) and poly(ε-caprolacton); poly(L-lactic acid) and poly(1,4-dioxan-2-one); poly(L-lactic acid) and poly(sebacic anhydride); poly(L-lactic acid) and poly(dodecanoic anhydride); poly(L-lactic acid) and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid); poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) and poly(L-lactic-co-glycolic acid); poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) and poly(ε-caprolacton); poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) and poly(1,4-dioxan-2-one); poly(butylcyanoacrylate) and poly(L-lactic-co-glycolic acid); poly(butylcyanoacrylate) and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid); poly(ethylcyanoacrylate) and poly(L-lactic-co-glycolic acid); poly(ethylcyanoacrylate) and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid); poly(ethylene glycol oxalate) and poly(L-lactic-co-glycolic acid); poly(ethylene glycol oxalate) and poly(ε-caprolacton); poly(ethylene glycol oxalate) and poly(1,4-dioxan-2-one); poly(ethylene glycol oxalate) and poly(sebacic anhydride); poly(ethylene glycol oxalate) and poly(dodecanoic anhydride); poly(ethylene glycol oxalate) and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid); dextran and poly(butylcyanoacrylate); dextran and poly(ethylcyanoacrylate); dextran and poly(L-lactic acid); dextran and poly(L-lactic-co-glycolic acid); dextran and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid); dextran and poly(sebacic anhydride); cellulose acetate and poly(L-lactic acid); cellulose acetate and poly(butylcyanoacrylate); cellulose acetate and poly(L-lactic-co-glycolic acid); cellulose acetate and poly(sebacic anhydride); and cellulose acetate and poly(dodecanoic anhydride); Carnauba wax and poly(lactide-co-glycolide); ethylcellulose and octadecanol; Carnauba wax and polycaprolactone; poly(methyl methacrylate) and poly(L-lactide); poly(lactide-co-glycolide) and poly(gelatin); silicone rubber and poly(L-lactide); ethylcellulose and a combination of poly(L-lactic-co-glycolic acid) and poly(ethylene glycol); a combination of poly(L-lactic acid) and dextran and a combination of poly(L-lactic-co-glycolic acid) and poly(ethylene glycol); and dextran and a combination of poly(L-lactide) and poly(L-lactic-co-glycolic acid).
 13. The controlled release composition of claim 1, wherein ΔT≧about 2° C.
 14. The controlled release composition of claim 1, wherein ΔT≧about 5° C.
 15. The controlled release composition of claim 1, wherein ΔT≧about 10° C. 16-19. (canceled)
 20. The controlled release composition of claim 1, wherein the first material is a biodegradable material.
 21. The controlled release composition of claim 1, wherein the second material is a biodegradable material.
 22. The controlled release composition of claim 21, wherein the second material degrades faster than the first material.
 23. The controlled release composition of claim 22, wherein the first material and the second material is a pair of materials selected from the group consisting of: poly (L-lactide acid) and poly(lactide-co-glycolide acid).
 24. The controlled release composition of claim 1, wherein the first active agent or the second active agent is independently selected from the group consisting of: local anesthetics, antiepileptic drugs and anticonvulsants, anti-alzheimer's disease drugs, analgesics, antipodagric, anti-hypertensive drugs, antiarrhythmic drugs, diuretic drugs, drugs for treating liver diseases, drugs for treating pancreatic diseases, antihistamine drugs, anti-allergic drugs, glucocorticoid drugs, sex hormone drugs and contraceptive drugs, hypoglycemic drugs, anti-osteoporosis drugs, antibiotics, sulfonamides, quinolones, and other synthetic antibacterial drugs, antituberculous drugs, antiviral drugs, anti-neoplasm drugs, immunomodulators, and cosmetically active agents.
 25. The controlled release composition of claim 1, wherein the microparticles comprise a weight percentage of about 2% to about 98% of the first material, and about 2% to about 98% of the first active agent.
 26. The controlled release composition of claim 1, wherein the microparticles further comprise a first additive.
 27. The controlled release composition of claim 26, wherein the weight percentage of the first additive in the microparticles ranges from about 0% to about 30%.
 28. The controlled release composition of claim 1, wherein at least one of the plurality of the microparticles further comprises a coating.
 29. The controlled release composition of claim 1, wherein the matrix further comprises a second active agent.
 30. The controlled release composition of claim 29, wherein the weight percentage of the second active agent in the controlled release composition ranges from about 0% to about 70%.
 31. The controlled release composition of claim 1, wherein the matrix further comprises a second additive.
 32. The controlled release composition of claim 31, wherein the weight percentage of the second additive in the controlled release composition ranges from about 0% to about 30%.
 33. The controlled release composition of claim 1, wherein controlled release composition comprises about 1% to about 95% of the microparticles.
 34. The controlled release composition of claim 1, wherein the plurality of microparticles are uniformly distributed or embedded in the matrix.
 35. The controlled release composition of claim 1, wherein the plurality of microparticles are distributed or embedded in the matrix in accordance with a pre-determined pattern.
 36. The controlled release composition of claim 1, wherein controlled release composition comprises a coating.
 37. The controlled release composition of claim 1, wherein at least one of the microparticles is of a size ranging from 1 μm to about 5000 μm. 38-40. (canceled)
 41. The controlled release composition of claim 1, wherein the controlled release composition is a pharmaceutical composition.
 42. The controlled release composition of claim 1, wherein the controlled release composition is an implantable pharmaceutical composition.
 43. A method for making a controlled release composition comprising a plurality of microparticles operably linked to a matrix, comprising the steps of: preparing a plurality of microparticles comprising a first material and a first active agent; and applying the plurality of microparticles to a matrix-forming composition, thereby forming the controlled release composition comprising a second material, wherein: the first material comprises an initial melting temperature T_(H); the second material comprises a complete melting temperature T_(L); ΔT=T_(H)−T_(L); and ΔT>0. 44-54. (canceled)
 55. A method of treating a condition in a subject, comprising administering to the subject a controlled release composition, wherein: the controlled release composition comprising a plurality of microparticles operably linked to a matrix; the plurality of microparticles comprises a first material and a first active agent; the matrix comprises a second material; the first material comprises an initial melting temperature T_(H); the second material comprises a complete melting temperature T_(L); ΔT=T_(H)−T_(L); and ΔT>0. 56-63. (canceled) 